Methods for preparing n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n&#39;-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form

ABSTRACT

Disclosed herein are methods for obtaining N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl) carbamide (pimavanserin) comprising the step of contacting an intermediate according to Formula (A) or a salt thereof, with an intermediate Formula B, or a salt thereof, to produce pimavanserin or a salt thereof wherein Y is —OR i  or —NR 2a R 2b ; R 3  is hydrogen or substituted or unsubstituted heteroalicyclyl, R 4  is substituted or unsubstituted aralkyl; X is —OR 22  or —NR 23 R 24 ; (wherein R 22  is hydrogen or substituted or unsubstituted C 1-6 alkyl and one of R 23  and R 24  is hydrogen and the other is hydrogen or N-methylpiperidin-4-yl); and R 21  is —OCH 2 CH(CH 3 ) 2  or F; Also disclosed herein is the tartrate salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl) carbamide and methods for obtaining the salt.

BACKGROUND Field

The present disclosure relates to the fields of medicine and chemistry.More particularly, the present disclosure relates one or more methods ofobtainingN-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide, its tartrate salt, and polymorphs, intermediates andsyntheses and uses thereof.

Description of the Related Art

N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide,also known as pimavanserin, is described in WO 2004/064738, WO2006/037043, WO 2007/124136 and WO 2008/144326, each of which isincorporated herein by reference in its entirety. These publicationsdescribe routes to prepare pimavanserin. Although the routes describedare sufficient to produce pimavanserin, there may be other routesproviding other opportunities.

SUMMARY

Disclosed herein include methods of preparing pimavanserin.

Disclosed herein are also intermediate products obtainable from themethods of preparing pimavanserin.

Disclosed herein are methods of preparing pimavanserin comprisingcontacting an intermediate according to Formula (A),

or a salt thereof, with an intermediate according to Formula (B).

or a salt thereof, to produce pimavanserin.

In certain embodiments, Y is selected from —OR₁ or —NR_(2a),R_(2b).

R₁, R_(2a), R_(2b), independently of each other are selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted aryl or R_(2a) and R_(2b) taken togetherwith the nitrogen to which they are attached form a substituted orunsubstituted heteroalicyclyl, substituted or unsubstituted aryl or asubstituted or unsubstituted heteroaryl.

R₃ is selected from hydrogen or substituted or unsubstitutedheteroalicyclyl.

R₄ is selected from substituted or unsubstituted aralkyl.

X is selected from the group consisting of —OR₂₂ and —NR₂₃R₂₄.

R₂₁ is selected from —OCH₂CH(CH₃)₂ or F.

R₂₂ is selected from hydrogen and substituted or unsubstituted C₁₋₆alkyl.

One of R₂₃ and R₂₄ is hydrogen and the other of R₂₃ and R₂₄ isN-methylpiperidin-4-yl, or both R₂₃ and R₂₄ are hydrogen.

In some embodiments, R₃ is substituted or unsubstituted heteroalicyclyl;R₂₁ is —OCH₂CH(CH₃)₂; R₂₃ is hydrogen; and R₂₄ is hydrogen.

In other embodiments, R₃ is hydrogen; R₂₁ is F; and one of R₂₃ and R₂₄is hydrogen and the other of R₂₃ and R₂₄ is N-methylpiperidin-4-yl.

In certain embodiments of the methods provided herein, R₁ is selectedfrom the group consisting of methyl, ethyl, propyl, butyl, pentyl,trifluoroethyl and phenyl.

In certain embodiments, R_(2a) and R_(2b) independently of each otherare selected from the group consisting of hydrogen, methyl, ethyl,propyl, butyl, pentyl, trifluoroethyl, p-nitrophenyl and phenyl. In someembodiments, R_(2a) and R_(2b) taken together with the nitrogen to whichthey are attached form a substituted or unsubstituted imidazolyl,substituted or unsubstituted benzotriazole, substituted or unsubstitutedpyrrolyl, substituted or unsubstituted morpholinyl.

In some embodiments, the intermediate according to Formula (A) is acompound according to Formula (A2):

and the intermediate according to Formula (B) is a compound according toFormula (B2):

In some embodiments, the intermediate according to Formula (A) is acompound according to Formula (A3):

and the intermediate according to Formula (B) is a compound according toFormula (B3):

In some embodiments, Y is —OR₁ and R₁ is selected from the groupconsisting of methyl, ethyl, propyl, butyl, pentyl, trifluoroethyl andphenyl. In some embodiments, R₁ is phenyl.

In some embodiments, Y is NR_(2a)R_(2b), wherein R_(2a) and R_(2b) takentogether with the nitrogen to which they are attached form a substitutedor unsubstituted imidazolyl.

Disclosed herein is also a method of synthesizing the compound accordingto Formula (I), i.e.,N-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxy)phenylmethyl) carbamide, i.e., pimavanserin, as a tartrate salt,comprising reactingN-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxy)phenylmethyl) carbamide with tartaric acid in the presence of a solvent,e.g., ethanol. In certain embodiments, the tartrate salt is ahemi-tartrate salt. In some embodiments the pimavanserin tartrate is ahemi-tartrate having a molecular weight of 1005.2.

In other aspects, provided herein is a compound according to Formula(A):

or salt, hydrate, solvate, polymorph, or stereoisomers thereof, whereinY, R₃ and R₄ are as defined below.

In some embodiments, Y is selected from —OR₁ or —NR_(2a),R_(2b).

R₁, R_(2a), R_(2b), independently of each other are selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,or R_(2a) and R_(2b) taken together with the nitrogen to which they areattached form a substituted or unsubstituted heteroalicyclyl,substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl.

R₃ is selected from hydrogen or substituted or unsubstitutedheteroalicyclyl.

R₄ is selected from substituted or unsubstituted aralkyl.

In some embodiments, the compound according to Formula (A) is selectedfrom the group consisting of Formula (C)-(F):

wherein R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₁ are as defined below.

In some embodiments, R₁₀ and R₁₁ are selected from hydrogen, substitutedor unsubstituted C₁₋₆ alkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted aralkyl.

In some embodiments, R₁₂, R₁₃, R₁₄, and R₁₅ independently of each otherare selected from hydrogen, substituted or unsubstituted C₁₋₆ alkyl, andsubstituted or unsubstituted aralkyl.

In certain embodiments, R₁₂ and R₁₃ taken together with the nitrogen towhich they are attached form a substituted or unsubstitutedheteroalicyclyl, substituted or unsubstituted aryl or a substituted orunsubstituted heteroaryl.

In certain embodiments, R₁₄ and R₁₅ taken together with the nitrogen towhich they are attached form a substituted or unsubstitutedheteroalicyclyl, substituted or unsubstituted aryl or a substituted orunsubstituted heteroaryl.

In some embodiments, R₁₀ is selected from methyl, ethyl, trifluoroethyl,pentyl, and phenyl; R₁₁ is selected from methyl, ethyl, trifluoroethyl,pentyl, and phenyl; R₁₂, R₁₃, R₁₄, R₁₅ are hydrogen.

In some embodiments, R₁₂ and R₁₃ taken together with the nitrogen towhich they are attached form an imidazolyl or benzotriazole.

In some embodiments, R₁₄ and R₁₅ taken together with the nitrogen towhich they are attached form an imidazolyl or benzotriazole.

In certain embodiments, the compound is a compound according to Formula(C) or (D), wherein R₁₀ and R₁₁ are each selected from phenyl.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety. In the event that there is a plurality of definitions for aterm herein, those in this section prevail unless stated otherwise.

As used herein, any “R” group(s) such as, without limitation, R₁, R₂,R₃, R₄, R₅, R₈, R₉, and R₁₀, represent substituents that can be attachedto the indicated atom. A non-limiting list of R groups includes but arenot limited to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl. Iftwo “R” groups are covalently bonded to the same atom or to adjacentatoms, then they may be “taken together” or “combined to” as definedherein to form a cycloalkyl, aryl, heteroaryl or heteroalicyclyl group.For example, without limitation, if R_(a) and R_(b) of an NR_(a)R_(b)group are indicated to be “taken together” or “combined to”, it meansthat they are covalently bonded to one another at their terminal atomsto form a ring that includes the nitrogen:

Whenever a group is described as being “unsubstituted or substituted,”if substituted, the substituent(s) (which may be present one or moretimes, such as 1, 2, 3 or 4 times, valencies permitting) areindependently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl,heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy,acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen,carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, includingmono- and di-substituted amino groups, and the protected derivativesthereof.

When a substituent is deemed to be “substituted,” the substituent itselfis substituted with one or more of the indicated substituents. When thereferenced substituent is substituted, it is meant that one or morehydrogen atoms on the referenced group may be replaced with a group(s)individually and independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl,hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto,alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido,N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl,sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, and amino, including mono- and di-substitutedamino groups, and the protected derivatives thereof. The protectinggroups that may form the protective derivatives of the abovesubstituents are known to those of skill in the art and may be found inGreene and Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed.,John Wiley & Sons, New York, N.Y., 1999, which is hereby incorporated byreference in its entirety.

As used herein, “C_(m) to C_(n),” “C_(m)-C_(n)” or “C_(m-n)” in which“m” and “n” are integers refers to the number of carbon atoms in therelevant group. That is, the group can contain from “m” to “n”,inclusive, carbon atoms. Thus, for example, a “C₁ to C₄ alkyl” grouprefers to all alkyl groups having from 1 to 4 carbons, that is, CH₃—,CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)—,CH₃CH(CH₃)CH₂— and (CH₃)₃C—. If no “m” and “n” are designated withregard to a group, the broadest range described in these definitions isto be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain group that is fully saturated (no double or triple bonds). Thealkyl group may have 1 to 20 carbon atoms (whenever it appears herein, anumerical range such as “1 to 20” refers to each integer in the givenrange; e.g., “1 to 20 carbon atoms” means that the alkyl group mayconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 20 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group may also be a medium size alkyl having 1 to10 carbon atoms, such as “C₁₋₆”. The alkyl group could also be a loweralkyl having 1 to 4 carbon atoms. The alkyl group of the compounds maybe designated as “C₁-C₄ alkyl,” “C₁₋₄ alkyl” or similar designations. Byway of example only, “C₁-C₄ alkyl” or “C₁₋₄ alkyl” indicates that thereare one to four carbon atoms in the alkyl chain, i.e., the alkyl chainis selected from the group consisting of methyl, ethyl, propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkylgroups include, but are in no way limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.When an alkyl is substituted, it can be substituted with one substituentor more than one substituent, where substituents are individually andindependently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl,(heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester,O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl,thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro,silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, includingmono- and di-substituted amino groups, and the protected derivativesthereof.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds. If morethan one double bond is present, the double bonds may be conjugated ornot conjugated. The alkenyl group may have 2 to 20 carbon atoms(whenever it appears herein, a numerical range such as “2 to 20” refersto each integer in the given range; e.g., “2 to 20 carbon atoms” meansthat the alkenyl group may consist of 2 carbon atom, 3 carbon atoms, 4carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkenyl”where no numerical range is designated). One or more substituents on asubstituted alkenyl are individually and independently selected fromalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl,(heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester,O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl,thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro,silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, includingmono- and di-substituted amino groups, and the protected derivativesthereof

As used herein, “alkynyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more triple bonds. Thealkynyl group may have 2 to 20 carbon atoms (whenever it appears herein,a numerical range such as “2 to 20” refers to each integer in the givenrange; e.g., “2 to 20 carbon atoms” means that the alkynyl group mayconsist of 2 carbon atom, 3 carbon atoms, 4 carbon atoms, etc., up toand including 20 carbon atoms, although the present definition alsocovers the occurrence of the term “alkynyl” where no numerical range isdesignated). An alkynyl group may be unsubstituted or substituted. Whensubstituted, the substituent(s) may be selected from the same groupsdisclosed above with regard to alkenyl group substitution.

As used herein, “hetero” may be attached to a group and refers to one ormore carbon atom(s) and the associated hydrogen atom(s) in the attachedgroup have been independently replaced with the same or differentheteroatoms selected from nitrogen, oxygen, phosphorus and sulfur.

As used herein, “heteroalkyl,” by itself or in combination with anotherterm, refers to a straight or branched alkyl group consisting of thestated number of carbon atoms, where one or more carbon atom(s), such as1, 2, 3 or 4 carbon atom(s), and the associated hydrogen atom(s) havebeen independently replaced with the same or different heteroatomsselected from nitrogen, oxygen and sulfur. The carbon atom(s) beingreplaced may be in the middle or at the end of the alkyl group. Examplesof heteroalkyl include, but are not limited to, —S-alkyl, —O-alkyl,—NH-alkyl, alkyl-O-alkyl, etc.

As used herein, “aryl” refers to a carbocyclic (all carbon) ring or twoor more fused rings (rings that share two adjacent carbon atoms) thathave a fully delocalized pi-electron system. Examples of aryl groupsinclude, but are not limited to, benzene, naphthalene and azulene. Anaryl group may be substituted. When substituted, hydrogen atoms arereplaced by substituent group(s) that is(are) one or more group(s)independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl,heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy,acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen,carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, includingmono- and di-substituted amino groups, and the protected derivativesthereof. When substituted, substituents on an aryl group may form anon-aromatic ring fused to the aryl group, including a cycloalkyl,cycloalkenyl, cycloalkynyl, and heterocyclyl.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem), in which at least one of the atoms in the ring system is aheteroatom, that is, an element other than carbon, including but notlimited to, nitrogen, oxygen and sulfur. Examples of “heteroaryl”include, but are not limited to, furan, thiophene, phthalazine, pyrrole,oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole,triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine,tetrazole, and triazine. A heteroaryl may be substituted. Whensubstituted, hydrogen atoms are replaced by substituent group(s) thatis(are) one or more group(s) independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl,hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto,alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido,N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl,sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, and amino, including mono- and di-substitutedamino groups, and the protected derivatives thereof. When substituted,substituents on a heteroaryl group may form a non-aromatic ring fused tothe aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, andheterocyclyl.

An “aralkyl” or “arylalkyl” is an aryl group connected, as asubstituent, via an alkylene group. The alkylene and aryl group of anaralkyl may be substituted. Examples include but are not limited tobenzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, andnaphthylalkyl. In some cases, the alkylene group is a lower alkylenegroup.

A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, asa substituent, via an alkylene group. The alkylene and heteroaryl groupof heteroaralkyl may be substituted. Examples include but are notlimited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl,pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, pyrazolylalkyl andimidazolylalkyl, and their substituted as well as benzo-fused analogs.In some cases, the alkylene group is a lower alkylene group.

An “alkylene” is a straight-chained tethering group, forming bonds toconnect molecular fragments via their terminal carbon atoms. Thealkylene may have 1 to 20 carbon atoms. The alkylene may also be amedium size alkylene having 1 to 10 carbon atoms, such as “C₁₋₆”. Thealkylene could also be a lower alkylene having 1 to 4 carbon atoms. Thealkylene may be designated as “C₁-C₄ alkylene”, “C₁₋₄ alkylene” orsimilar designations. Non-limiting examples include, methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), and butylene (—(CH₂)₄—)groups. In the case of methylene, the two connected fragments areconnected to the same carbon atom. A lower alkylene group may besubstituted.

As used herein, “heteroalkylene” by itself or in combination withanother term refers to an alkylene group consisting of the stated numberof carbon atoms in which one or more of the carbon atoms, such as 1, 2,3 or 4 carbon atom(s), are independently replaced with the same ordifferent heteroatoms selected from oxygen, sulfur and nitrogen.Examples of heteroalkylene include, but not limited to —CH₂—O—,—CH₂—CH₂—O—, —CH₂—CH₂—CH₂—O—, —CH₂—NH—, —CH₂—CH₂—NH—, —CH₂—CH₂—CH₂—NH—,—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH₂—O—CH₂—CH₂—O—, —O—CH₂—CH₂—O—CH₂—CH₂—, andthe like.

As used herein, “alkylidene” refers to a divalent group, such as ═CR′R″,which is attached to one carbon of another group, forming a double bond.Alkylidene groups include, but are not limited to, methylidene (═CH₂)and ethylidene (═CHCH₃). As used herein, “arylalkylidene” refers to analkylidene group in which either R′ or R″ is an aryl group. Analkylidene group may be substituted.

As used herein, “alkoxy” refers to the group —OR wherein R is an alkyl,e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy),cyclopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy,tert-amoxy and the like. An alkoxy may be substituted.

As used herein, “alkylthio” refers to the formula —SR wherein R is analkyl defined as above, e.g., methylmercapto, ethylmercapto,n-propylmercapto, 1-methyl ethyl mercapto (isopropylmercapto),n-butylmercapto, iso-butylmercapto, sec-butylmercapto,tert-butylmercapto, and the like. An alkylthio may be substituted.

As used herein, “aryloxy” and “arylthio” refers to RO— and RS—, in whichR is an aryl as defined above, e.g., phenoxy, naphthalenyloxy,azulenyloxy, anthracenyloxy, naphthalenylthio, phenylthio and the like.Both an aryloxy and arylthio may be substituted.

As used herein, “alkenyloxy” refers to the formula —OR wherein R is analkenyl as defined above, e.g., vinyloxy, propenyloxy, n-butenyloxy,iso-butenyloxy, sec-pentenyloxy, tert-pentenyloxy, and the like. Thealkenyloxy may be substituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, oraryl connected, as substituents, via a carbonyl group. Examples includeformyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may besubstituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doublebonds) mono- or multi-cyclic hydrocarbon ring system. When composed oftwo or more rings, the rings may be joined together in a fused, bridgedor spiro-connected fashion. Cycloalkyl groups may range from C₃ to C₁₀,in other embodiments it may range from C₃ to C₆. A cycloalkyl group maybe unsubstituted or substituted. Typical cycloalkyl groups include, butare in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like. If substituted, the substituent(s) may be analkyl or selected from those indicated above with regard to substitutionof an alkyl group unless otherwise indicated. When substituted,substituents on a cycloalkyl group may form an aromatic ring fused tothe cycloalkyl group, including an aryl and a heteroaryl.

As used herein, “cycloalkenyl” refers to a cycloalkyl group thatcontains one or more double bonds in the ring although, if there is morethan one, they cannot form a fully delocalized pi-electron system in thering (otherwise the group would be “aryl,” as defined herein). Whencomposed of two or more rings, the rings may be connected together in afused, bridged or spiro-connected fashion. A cycloalkenyl group may beunsubstituted or substituted. When substituted, the substituent(s) maybe an alkyl or selected from the groups disclosed above with regard toalkyl group substitution unless otherwise indicated. When substituted,substituents on a cycloalkenyl group may form an aromatic ring fused tothe cycloalkenyl group, including an awl and a heteroaryl.

As used herein, “cycloalkynyl” refers to a cycloalkyl group thatcontains one or more triple bonds in the ring. When composed of two ormore rings, the rings may be joined together in a fused, bridged orspiro-connected fashion. Cycloalkynyl groups may range from C₈ to C₁₂. Acycloalkynyl group may be unsubstituted or substituted. Whensubstituted, the substituent(s) may be an alkyl or selected from thegroups disclosed above with regard to alkyl group substitution unlessotherwise indicated. When substituted, substituents on a cycloalkynylgroup may form an aromatic ring fused to the cycloalkynyl group,including an aryl and a heteroaryl.

As used herein, “heteroalicyclic” or “heteroalicyclyl” refers to a 3- to18 membered-ring which consists of carbon atoms and from one to fiveheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. The heteroalicyclic or heteroalicyclyl groups may range from C₃to C₁₀, in other embodiments it may range from C₃ to C₉ and in otherembodiments it may range from C₃ to C₈. The “heteroalicyclic” or“heteroalicyclyl” may be monocyclic, bicyclic, tricyclic, or tetracyclicring system, which may be joined together in a fused, bridged orspiro-connected fashion; and the nitrogen, carbon and sulfur atoms inthe “heteroalicyclic” or “heteroalicyclyl” may be oxidized; the nitrogenmay be quaternized; and the rings may also contain one or more doublebonds provided that they do not form a fully delocalized pi-electronsystem throughout all the rings. Heteroalicyclyl groups may beunsubstituted or substituted. When substituted, the substituent(s) maybe one or more groups independently selected from the group consistingof alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl,(heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester,O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, C-amido,N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato,isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, includingmono- and di-substituted amino groups, and the protected derivativesthereof. Examples of such “heteroalicyclic” or “heteroalicyclyl” includebut are not limited to, azepinyl, azetidinyl, dioxolanyl, imidazolinyl,imidazolinolyl morpholinyl, oxetanyl, oxiranyl, piperidinyl N-oxide,piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and4-piperidinyl), pyrrolidinyl, (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and3-pyrrolidinyl), piperazinyl, pyranyl, 4-piperidonyl, tetrahydrofuranyl,tetrahydropyranyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. Whensubstituted, substituents on a heteroalicyclyl group may form anaromatic ring fused to the heteroalicyclyl group, including an aryl anda heteroaryl.

A “(cycloalkyl)alkyl” is a cycloalkyl group connected, as a substituent,via an alkylene group. The alkylene and cycloalkyl of a(cycloalkyl)alkyl may be substituted. Examples include but are notlimited cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl,cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl,cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl,cycloheptylmethyl, and the like. In some cases, the alkylene group is alower alkylene group.

A “(cycloalkenyl)alkyl” is a cycloalkenyl group connected, as asubstituent, via an alkylene group. The alkylene and cycloalkenyl of a(cycloalkenyl)alkyl may be substituted. In some cases, the alkylenegroup is a lower alkylene group.

A “(cycloalkynyl)alkyl” is a cycloalkynyl group connected, as asubstituent, via an alkylene group. The alkylene and cycloalkynyl of a(cycloalkynyl)alkyl may be substituted. In some cases, the alkylenegroup is a lower alkylene group.

As used herein, “halo” or “halogen” refers to F (fluoro), Cl (chloro),Br (bromo) or I (iodo).

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by halogen. Such groups includebut are not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. Ahaloalkyl may be substituted.

As used herein, “haloalkoxy” refers to a RO-group in which R is ahaloalkyl group. Such groups include but are not limited to,chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. A haloalkoxy may besubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or(heteroalicyclyl)alkyl, as defined herein. An O-carboxy may besubstituted.

A “C-carboxy” group refers to a “—C(═O)OR” group in which R can be thesame as defined with respect to O-carboxy. A C-carboxy may besubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group” wherein Xis a halogen.

A dashed bond, represents an optional unsaturation between the atomsforming the bond. This bond may be unsaturated (e.g., C═C, C═N, C═O) orsaturated (e.g., C—C, C—N, C—O). When a dashed bond is present in a ringsystem it may form part of an aromatic ring system.

A “nitro” group refers to a “—NO₂” group.

A “cyano” group refers to a “—CN” group.

A “cyanato” group refers to an “—OCN” group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—SCN” group.

A “carbonyl” group refers to a “—C(═O)—” group.

A “thiocarbonyl” group refers to a “—C(═S)—” group.

An “oxo” group refers to a “═O” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to O-carboxy. A sulfinyl may besubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to O-carboxy. A sulfonyl may be substituted.

An “S-sulfonamido” group refers to a “—SO₂NR_(A)R_(B)” group in whichR_(A) and R_(B) independently of each other can be the same as definedwith respect to the R group as defined for O-carboxy, or combined toform a ring system selected from the group consisting of substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈cycloalkenyl, substituted or unsubstituted C₃₋₈ cycloalkyl, substitutedor unsubstituted C₃₋₈ cycloalkenyl, substituted or unsubstitutedheteroalicyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl. An S-sulfonamido may be substituted.

An “N-sulfonamido” group refers to a “RSO₂N(R_(A))—” group in which Rand R_(A) independently of each other can be the same as defined withrespect to the R group as defined for O-carboxy. An N-sulfonamido may besubstituted.

A “trihalomethanesulfonamido” group refers to an “X₃CSO₂N(R)—” groupwith X as halogen and R can be the same as defined with respect toO-carboxy. A trihalomethanesulfonamido may be substituted.

A “C-amido” group refers to a “—C(═O)NR_(A)R_(B)” group in which R_(A)and R_(B) independently of each other can be the same as defined withrespect to the R group as defined for O-carboxy, or combined to form aring system selected from the group consisting of substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈cycloalkenyl, substituted or unsubstituted C₃₋₈ cycloalkyl, substitutedor unsubstituted C₃₋₈ cycloalkenyl, substituted or unsubstitutedheteroalicyclyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl. A C-amido may be substituted.

An “N-amido” group refers to a “RC(═O)NR_(A)—” group in which R andR_(A) independently of each other can be the same as defined withrespect to the R group as defined for O-carboxy. An N-amido may besubstituted.

An “ester” refers to a “—C(═O)OR” group in which R can be the same asdefined with respect to O-carboxy. An ester may be substituted.

A lower alkoxyalkyl refers to an alkoxy group connected via a loweralkylene group. A lower alkoxyalkyl may be substituted.

An “amino” refers to “RNH₂” (primary amines), “R₂NH” (secondary amines),and “R₃N” (tertiary amines). An amino group may be substituted.

An aminoalkyl refers to an amino group connected via a alkylene group. Aaminoalkyl may be substituted.

Any unsubstituted or monosubstituted amine group on a compound hereincan be converted to an amide, any hydroxyl group can be converted to anester and any carboxyl group can be converted to either an amide orester using techniques well-known to those skilled in the art (see, forexample, Greene and Wuts, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley & Sons, New York, N.Y., 1999).

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

Herein are thus described methods of obtaining pimavanserin as well asnovel compounds used as intermediates in the preparation ofpimavanserin. Pimavanserin, salts and polymorphs thereof, as well asmethods of obtaining pimavanserin has previously been described in forexample WO 2004/064738, WO 2006/037043, WO 2007/124136 and WO2008/144326.

Pimavanserin has the chemical formula (I)

Optionally pimavanserin can be referred to as(N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyl oxy)phenylmethyl)carbamide).

The compound of formula I can be obtained by the methods describedherein in high purity and yields. High purity is herein defined as apurity of at least 70%, such as at least 80%, such as at least 90%, suchas at least 92%, such as at least 94%, such as at least 96%, such as atleast 98%, such as at least 99%. According to some embodiments hereinpimavanserin is obtained as a tartrate salt. According to someembodiments the pimavanserin tartrate is pimavanserin hemi-tartrate.According to some embodiments the pimavanserin tartrate is polymorphicForm C.

In some embodiments pimavanserin tartrate is obtained in a purity of atleast 96%, e.g. at least 98% based on HPLC (high performance liquidchromatography).

In some embodiments pimavanserin tartrate in polymorphic Form C isobtained in a purity of at least 98%, e.g. at least 99% based on HPLC.

According to methods disclosed herein pimavanserin is possible toproduce in large scale. Some of the routes described herein have shownparticular usefulness when it comes to producing pimavanserin in largescale manufacturing, i.e., suitable for preparing pharmaceuticalcompositions of pimavanserin.

Pimavanserin has previously been synthesized according to the methoddisclosed in Scheme I.

As demonstrated in the examples provided herein, there are other methodssuitable to prepare pimavanserin. Such methods may, for example, resultin an improved manufacturing process, e.g., scalability for large scaleproduction, improved purity, improved sourcing of materials, and/orimproved environmental profile, etc.

In some aspects disclosed herein, methods of preparing pimavanserin usestarting materials that differ from those in Scheme I.

For instance, starting materials used in the methods described herein,such as those designated as SM1(N-(4-fluorobenzyl)-1-methylpiperidin-4-amine) and SM2((4-isobutoxyphenyl)methanamine), may be obtained by any route andthereafter, e.g., as disclosed herein, converted in one or more stepsinto pimavanserin. Some useful routes for preparing SM1 and SM2 aredisclosed in the exemplary section.

Examples of methods of producing pimavanserin are summarized below.

Pimavanserin (1) may be manufactured by reacting SM1 with a carbamatederivative of SM2, as depicted in Scheme II.

Alternatively, pimavanserin may be manufactured by reacting SM2 with acarbamate derivative of SM1, as depicted in Scheme III.

More specifically, pimavanserin may be manufactured via activation of adialkyl carbonate or a diaryl carbonate, e.g., by reacting SM1 and SM2,or the freebase of SM2b with a suitable carbonate such as dimethylcarbonate, ethylmethyl carbonate, diethyl carbonate, disuccinimidylcarbonate, dimethyl 2,2′-(carbonylbis(oxy))dibenzoate or diphenylcarbonate in order to obtain, and optionally isolate a carbamate ofeither SM1 or SM2, e.g., as shown in the following structures (where“Me” is methyl and “Ph” is phenyl).

I1, I1.1, I2, I2.1, I2.3 or another suitable carbamate is then reactedwith SM2 or SM1 respectively to obtain pimavanserin. In addition to thecarbonates mentioned above, other suitable carbonates may be used. Insome embodiments dimethyl carbonate (DMC) is used. DMC is useful as itgenerates methanol as by-product and the catalyst may be recycledresulting in an environmentally beneficial route. Additionally, a routeemploying DMC could be preferred compared to the conventional processboth economically and for process safety reasons. In some embodimentsdiphenyl carbonate is used, in which case the easily separatedco-product is phenol. In some embodiments the reaction is run using thecarbonate as a solvent and in some embodiments another suitable solventis used, e.g., toluene and THF. To improve yields and conversions,catalysts such as NaO^(t)Bu and Zr(O^(t)Bu)₄ are used. In someembodiments co-catalysts such as 2-hydroxypyridine and4-methyl-2-hydroxyquinoline are used. In some embodiments the carbamateof SM1 or SM2 (or free-based SM2b) may be prepared by reacting SM1 orSM2 respectively with a slight excess (e.g., 1.1 to 2 eq) of diphenylcarbonate in a suitable solvent such as toluene or acetonitrile. Themixture may then be stirred for at suitable time such as 1-24 h at asuitable temperature such as room temperature. In one embodiment SM2 orSM2b (which may be freebased) is converted to a carbonate according toany of the methods described above.

Pimavanserin may also be manufactured via a chloroformate reagent, e.g.,by reacting either SM1 or SM2 (or free-based SM2b) with a suitablechloroformate such as an alkyl chloroformate (e.g., methylchloroformate, ethyl chloroformate, trifluoroethyl chloroformate), or anaryl chloroformate (e.g., phenyl chloroformate) in order to obtain, andoptionally isolate a carbamate of either SM1 or SM2, as shown above (ILI1.1, 12, and 12.1) and in the following structures:

I1, I1.1, I1.2, I2, I2.1 I2.2 or another suitable carbamate isthereafter reacted with SM2 or SM1 respectively to obtain pimavanserin.The carbamate of SM1 may for example be prepared by dissolving SM1 in asuitable amount of toluene or THF and adding a suitable base such aspotassium carbonate (e.g., dissolved in water) or sodium hydridesuspended in THF. Suitable equivalents of base are for example 1-2 eq.To the mixture containing SM1 a suitable chloroformate such as phenylchloroformate (e.g., 1-2 eq) whereafter the mixture for example may bestirred at a suitable temperature, such as room temperature, for asuitable time such as 6-36 h. The carbamate of SM2 or SM2b may forexample be prepared by adding a slight excess of phenyl chloroformate toSM2 or SM2b (which is free-based, e.g., using sodium hydroxide intoluene) dissolved in a suitable solvent such as toluene or THF, whereinthe mixture additionally comprises an excess (e.g., 1-2 eq) of asuitable base such as triethyl amine, sodium hydroxide or sodiumcarbonate. The mixture is for example maintained at a low temperature,such as −3 to 10° C., or at temperature of about 20-50° C. (depending onwhat base is used) for about 1 hour or longer in order to generate thecarbamate of SM2 or SM2b in high purity (e.g., >90%). In addition to thechloroformates mentioned above other suitable chloroformates may beused.

In one embodiment the formed carbamate is the carbamate of formula I1.1,

The carbamate of formula I1.1 is characterized for example by a DSCmelting point at 99° C. and an exothermic event of 48 J/g at about 191°C., which were determined using a DSC822e Differential Scanningcalorimeter (Mettler Toledo, Columbus Ohio) following the manufacturer'srecommended standard procedures and conditions.

In one embodiment, SM2 or SM2b is synthesized by one of the routesdepicted in Scheme IV. These routes have the advantage of using isobutylalcohol as a reagent instead of the previously used isobutyl bromide(e.g., Scheme 1), which is an alkylating agent known to be a healthhazard and a potential genotoxin. In one embodiment SM2 or SM2b issynthesized using the starting materials isobutyl alcohol and4-fluorobenzonitrile.

In some embodiments the conversion into I1.1 is complete and in someembodiments minor amounts (e.g., less than 5%, such as less than 3%,such as less than 1%, such as less than 0.5%) of the impurity1,3-bis(4-isobutoxybenzyl)urea, and less than 10%, such as less than 5%,such as less than 3%, such as less than 1% of the impurity phenol areobserved. Typically the yield of I1.1 is at least 85%, such as at least88%, such as at least 90%.

One of I1, I1.1, I1.2, I2, I2.1 I2.2 (carbamate intermediates) isthereafter reacted with the appropriate SM1, SM2 (SM2b or the freebaseof SM2b), to obtain pimavanserin.

The carbamate routes, i.e., those routes forming pimavanserin via acarbamate intermediate provide benefits such as facilitated sourcing,improved environmental profile, reduced cost and require lesscomplicated handling of reagents as compared to the conventionally usedroute currently used to form pimavanserin. In contrast to the priorsyntheses of pimavanserin (e.g., Scheme 1), the use of carbamateintermediates avoids the direct employment of phosgene, which is a toxicreagent. Phosgene in GMP production is generally to be avoided as knownto those skilled in the art. The carbamates routes, for example, theroute described herein where SM2 or SM2b, generated from4-fluorobenzonitrile and isobutanol, and brought in contact with phenylchloroformate to generate I1.1, which thereafter is converted topimavanserin, or a salt thereof, such as a pharmaceutically acceptablesalt thereof, e.g. a hemi-tartrate salt, have several advantages alreadymentioned and result in a cheaper and shorter process, and avoid toxicstarting materials. The process can be run as a single operation, ormultiple operations and hence provide further flexibility in view ofpotential production sites. For example, using 4-fluorobenzonitrile asstarting material provides a facilitated process as it is possible togenerate SM2 and SM2b in “one pot”. As mentioned there is no need forisobutyl bromide and the process requires less process steps to generateSM2 and/or SM2b compared to other disclosed routes of preparingpimavanserin. The process can be run to generate pimavanserin tartrateas polymorph C without isolating any intermediate product prior to thesalt and/or polymorph generation.

Examples of suitable solvents for generating the carbamate intermediatesare polar and non-polar aprotic solvents. More specific examples areacetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran,dimethylformamide, hexane, chloroform, dichloromethane, ethers (e.g.,diethyl ether, diisopropyl ether, methyl tert-butyl ether), ethylacetate, toluene, ethyl acetate, isopropyl acetate, and water. Accordingto some aspects the solvent should be less than 50 vol % compared to theother constituents in order to obtain improved conversion of thestarting materials. In some embodiments toluene or isopropyl acetate isselected as the solvent.

Although the reaction may be run without an additional agent, such as acatalyst, some embodiments include one or more additional agent(s) suchas a base, e.g., triethyl amine, diisopropyl amine, pyridine or alkalimetal carbonates, such as sodium carbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide, sodium phosphate or potassium phosphate.The agent(s) may provide improved conversion time.

Although the reaction may be run without the above listed additionalagent(s) at room temperature, it is generally considered that anincreased temperature provides a faster completion rate, howeveradditional amounts of impurities may be generated. Examples of suitableagents are a base, such as triethyl amine or alkali metal salts, such assodium carbonate or potassium carbonate. The agent when used in suitableamounts such as 0.1-5 eq, for example 0.5-1.5 eq, such as 1 eq improvedthe conversion time and resulted in improved yield. In some embodimentspotassium carbonate is selected as the catalyst as it has shown toreduce the amount of the impurity 1,3-bis(4-isobutoxybenzyl)urea. Insome embodiments the potassium carbonate is used in 0.4-1 eq. In someembodiments the temperatures used to carry out the formation of thecarbamate intermediate are from −3° C. to 50° C., for example between5-25° C., such as between 15-23° C. Additionally, heating is used insome embodiments in order to achieve phase separation, and suitabletemperatures are above 40° C., 50° C., 60° C., 70° C., 80° C., 90° C.,100° C. or 110° C. In some embodiments the temperature is kept at about65° C., 85° C., or 105° C. In some embodiments room temperature is used.

In some embodiments coupling of the carbamate intermediates with asecond starting material is carried out using a slight excess of one ofthe starting materials, for example a 1:1.1 to 1:1.5 ratio. In someembodiments disclosed herein an excess of either starting material isused, Alternatively a 1:1 ratio of the carbamate intermediate and thesecond starting material is used in order to limit formation ofimpurities, as well as unreacted starting materials in the crudeproduct. The carbamate may be an isolated intermediate or anintermediate generated in-situ (i.e. not isolated).

In some embodiments conversion of the starting materials intopimavanserin, using the above described conditions, is completed within24 h, such as within 3-8 hours, such as within 4-6 hours.

In one embodiment, I1.1 (e.g., obtained via reacting SM2 with phenylchloroformate or diphenyl carbonate) was mixed (1:1) with SM1 in tolueneand about 0.5 eq potassium carbonate (K₂CO₃) in order to generatepimavanserin. The HPLC purity of the obtained pimavanserin can be above99%, such as above 99.5%, such as about 99.6%, such as about 99.7%, suchas about 99.8%, such as about 99.9%; and the yield can be above 90%,such as above 92%, such as about 94%, such as about 96%. Additionally,pimavanserin obtained via phenyl chloroformate or diphenyl carbonateroutes are above 85% or about 90% or more.

In one embodiment the carbamate intermediate is obtained using acarbonate reagent, for example diphenyl carbonate. In one embodiment thecarbamate intermediate is obtained using a chloroformate reagent, forexample phenyl chloroformate.

Generating pimavanserin using any of the above described carbamateroutes (i.e., those employing a carbamate intermediate) may be done bymixing the carbamate with SM1 or SM2 (depending on what carbamateintermediate is used). Generally the reaction can be carried out at atemperature of up to 100° C. In some embodiments the temperature is50-60° C. In some embodiments one or more additional agent(s), forexample a base such as an alkali metal carbonate (e.g., sodium carbonateor potassium carbonate), or an organic base such as triethyl amine isused. In some embodiments potassium carbonate is used as it reduces theconversion time. Generally the reaction is carried out within 24 hours,but using an alkali metal carbonate such as potassium carbonate as anadditional agent has made it possible to reduce the reaction time toabout 4-6 h.

Examples of suitable solvents for generating pimavanserin are polar andnon-polar aprotic solvents. More specific examples are acetonitrile,tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide, hexane,chloroform, dichloromethane, ethers (e.g., diethyl ether, diisopropylether or methyl tert-butyl ether), ethyl acetate, toluene, ethylacetate, isopropyl acetate or water. In some embodiments toluene orisopropyl acetate is used as solvent.

Pimavanserin may also be manufactured via reaction of SM2 or SM1 withcarbonyldiimidazole (CDI) or 1,1′ carbonylbisbenzotriazole, formingintermediates I4, I4.1, I6 and I6.1 respectively. The intermediates maybe isolated and characterized and accordingly have the followingformulas:

I4, I4.1, is reacted with SM1; alternatively I6 or I6.1 is reacted withSM2 to obtain pimavanserin. In some embodiments the process to producepimavanserin goes via the formation of I6. The intermediate I6 may forexample be prepared by dissolving SM2b in water containing sodiumhydroxide (about 30%), and adding toluene, followed by heating themixture to obtain separated layers and then separating the layers, e.g.,by distillation. To CDI (slight excess, e.g., 1.2-1.8 eq) in toluene wasadded the previously obtained SM2 while the temperature was kept aroundroom temperature. Layer separation was performed once the reaction hadgone to completion by addition of water at a temperature below 15° C.,and I6 obtained from the organic phase by conventional methods. Theintermediate may be isolated or telescoped directly into the next stepwhere it is converted into pimavanserin by adding SM1 and heating (e.g.,at about 50° C.) the mixture in toluene followed by aqueous work-up andcollecting pimavanserin in the organic phase.

Advantages using CDI, are for example operational safety andsurprisingly a simplified process (e.g., fewer impurities) making theroute preferred compared to the conventional process shown in Scheme 1.

Pimavanserin may also be manufactured via reaction of SM2 withdi-tert-butyl dicarbonate (Boc₂O), forming intermediate I7. Theintermediate may be isolated as a compound having the formula:

Intermediate I7 thereafter may be reacted with SM1 with catalyticamounts of DMAP (4-dimethylaminopyridine) to obtain pimavanserin.

Pimavanserin may also be manufactured via reaction with a suitable ureaderivative or carbamate derivative. SM1 or SM2 may be reacted with aurea derivative such as urea and thereafter optionally isolated orreacted with SM2 or SM1 respectively in order to obtain pimavanserin. Asimilar option would be to react SM2 with urea and 3-methylbutan-1-01 togive isopentyl (4-isobutoxybenzyl)carbamate (18) which can be convertedto an isocyanate intermediate, 1-isobutoxy-4-(isocyanotomethyl)benzene(19), by distillation at temperature 160-180° C. The isocyanate 19 canbe reacted with SM1 to obtain pimavanserin.

Pimavanserin may also be manufactured via treatment of SM1 or SM2 with asuitable carbamate. Examples of suitable carbamates are alkyl carbamatessuch as methyl carbamate, and ethyl carbamate. Consequentlyintermediates of for example formulae (I10) and (I11) may be isolated ordirectly reacted with SM2 or SM1 respectively in order to obtainpimavanserin.

Intermediates I10 and I11 can then be reacted with a suitable aldehydeor hydroxyl moiety.

Publications such as J. Am. Chem. Soc., 1923, 45, 1816; Chem Ber 1965,98, 1097; and Org Prep Proc 1986, 18, 149, in general, disclosereactions conditions and procedures suitable to generate ureas andcarbamates.

The methods described above to generate pimavanserin may be furthercomplemented by obtaining pimavanserin in different salt forms, such astartrate salt. Of general interest are routes for obtaining SM1 and SM2respectively. For example obtaining SM1 and SM2 respectively fromdifferent starting material would be of interest and within the capacityof those skilled in the art. For example obtaining SM1 as a salt such asa hydrochloric or tartaric salt may confer benefits. A describedadvantages in view of sourcing and toxicity may also impact theselection of raw materials and for example(4-isobutoxyphenyl)methanamine may be prepared using different rawmaterials, for example 4-fluorobenzonitrile and isobutanol, or4-hydroxybenzaldehyde and isobutyl bromide, or isobutylmethanesulfonate, or 4-fluorobenzaldehyde and isobutanol. In someembodiments the 4-fluorobenzonitrile and isobutanol is used to generate(4-isobutoxyphenyl)methanamine which may be used in preparingpimavanserin according to many of the routes described herein.

Some embodiments described herein relate to a method of preparingpimavanserin(N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide),the method comprising:

-   -   contacting an intermediate according to Formula (A),

-   -   or a salt thereof, with an intermediate according to Formula        (B), or a salt thereof,

-   -   or a salt thereof, to produce pimavanserin, wherein Y, R₃,R₄, X        and R₂₁ are as defined below.

Y is selected from —OR₁ or —NR_(2a),R_(2b).

R₁, R_(2a), R_(2b), independently of each other are selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted aryl; or R_(2a) and R_(2b) taken togetherwith the nitrogen to which they are attached form a substituted orunsubstituted heteroalicyclyl, substituted or unsubstituted aryl or asubstituted or unsubstituted heteroaryl.

R₃ is selected from hydrogen or substituted or unsubstitutedheteroalicyclyl.

R₄ is selected from substituted or unsubstituted aralkyl.

X is selected from the group consisting of —OR₂₂ and —NR₂₃R₂₄.

R₂₁ is selected from —OCH₂CH(CH₃)₂ or F.

R₂₂ is selected from hydrogen and substituted or unsubstituted C₁₋₆alkyl.

One of R₂₃ and R₂₄ is hydrogen and the other is N-methylpiperidin-4-yl,or both R₂₃ and R₂₄ are hydrogen.

Some embodiments relate to a method wherein R₁ is selected from thegroup consisting of methyl, ethyl, propyl, butyl, pentyl, trifluoroethyland phenyl.

Some embodiments relate to a method wherein R_(2a) and R_(2b)independently of each other are selected from the group consisting ofhydrogen, methyl, ethyl, propyl, butyl, pentyl, trifluoroethyl,p-nitrophenyl and phenyl, or R_(2a) and R_(2b) taken together with thenitrogen to which they are attached form a substituted or unsubstitutedimidazolyl, substituted or unsubstituted benzotriazole, substituted orunsubstituted pyrrolyl, substituted or unsubstituted morpholinyl. Thesubstituted or unsubstituted imidazolyl may according to someembodiments be selected from 1λ²-imidazole and1-methyl-1λ⁴,2λ²-imidazole.

Some embodiments relate to a method wherein the intermediate accordingto Formula (A) is a compound according to Formula (A2)

and the intermediate according to Formula (B) is a compound according toFormula (B2)

In some embodiments, the intermediate according to Formula (A) is acompound according to Formula (A3)

and the intermediate according to Formula (B) is a compound according toFormula (B3)

Some embodiments relate to Y being —OR₁, for example R₁ is methyl,ethyl, propyl, butyl, pentyl, trifluoroethyl and phenyl. In someembodiments R₁ is phenyl. In some embodiments the compound according toFormula (A2) or (A3) (where Y is —O-phenyl) is obtained using diphenylcarbonate or phenyl chloroformate.

Some embodiments relate to Y being NR_(2a)R_(2b), wherein R_(2a) andR_(2b) taken together with the nitrogen to which they are attached forma substituted or unsubstituted imidazolyl. In some embodiments thecompound according to Formula (A2) or (A3) (where Y is NR_(2a)R_(2b)) isobtained using CDI.

Some embodiments described herein relate to a method of preparingpimavanserin(N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide),the method comprising forming a an intermediate according to Formula(A),

or salts, hydrates, solvates, polymorphs, and stereoisomers thereof,wherein Y, R₃ and R₄ are as defined below:

Y is selected from —OR₁ or —NR_(2a),R_(2b);

R₁, R_(2a), R_(2b), independently of each other are selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted aryl or R_(2a) and R_(2b) taken togetherwith the nitrogen to which they are attached form a substituted orunsubstituted heteroalicyclyl, substituted or unsubstituted aryl or asubstituted or unsubstituted heteroaryl; R₃ is selected from hydrogenand substituted or unsubstituted heteroalicyclyl, and R₄ is selectedfrom substituted or unsubstituted aralkyl.

In some embodiments the compound according to Formula (A) is selectedfrom a compound according to Formula (C)-(F)

wherein R₁₀ and R₁₁ independently of each other are selected fromhydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted aryl, and substituted or unsubstituted aralkyl; and R₁₂,R₁₃, R₁₄, and R₁₅ independently of each other are selected fromhydrogen, substituted or unsubstituted C₁₋₆ alkyl, and substituted orunsubstituted aralkyl.

In certain embodiments wherein compound according to Formula (A) is acompound according to Formula (E), R₁₂ and R₁₃ taken together with thenitrogen to which they are attached form a substituted or unsubstitutedheteroalicyclyl, or a substituted or unsubstituted heteroaryl.

In certain embodiments wherein compound according to Formula (A) is acompound according to Formula (F), R₁₄ and R₁₅ taken together with thenitrogen to which they are attached form a substituted or unsubstitutedheteroalicyclyl, or a substituted or unsubstituted heteroaryl.

In some embodiments R₁₀ is selected from the group consisting of methyl,ethyl trifluoroethyl, pentyl, and phenyl. In some embodiments R₁₁ isselected from the group consisting of methyl, ethyl, trifluoroethyl,pentyl, and phenyl. In some embodiments R₁₂, R₁₃, R₁₄, R₁₅ are hydrogen.In some embodiments R₁₂ and R₁₃ taken together with the nitrogen towhich they are attached form an imidazolyl or benzotriazole. In someembodiments R₁₄ and R₁₅ taken together with the nitrogen to which theyare attached form an imidazolyl or benzotriazole.

In some embodiments the intermediate is a compound according to Formula(C) or (D).

In some embodiment R₁₀ is phenyl. In some embodiments the intermediateis a compound according to Formula (C) and R₁₀ is phenyl.

In some embodiments R₁₁ is phenyl. In some embodiments the intermediateis a compound according to Formula (D) and R₁₁ is phenyl.

In some embodiments the method comprises contacting 4-fluorobenzonitrileand isobutyl alcohol to provide 4-isobutoxy-benzonitrile, converting4-isobutoxy-benzonitrile to (4-isobutoxyphenyl)methanamine, contacting(4-isobutoxyphenyl)methanamine with phenylchloroformate, ordiphenylcarbonate, to give phenyl (4-isobutoxybenzyl)carbamate, andcontacting the phenyl (4-isobutoxybenzyl)carbamate withN-(4-fluorobenzyl)-1-methylpiperidin-4-amine providingN-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide.In some embodimentsN-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamideis obtained as a tartrate salt.

Accordingly the intermediate compounds described herein are used in thepreparation of pimavanserin and/or pimavanserin tartrate.

The compound of formula I (pimavanserin) has a low solubility in water.Accordingly, in some embodiments, salt forms of the compound areprovided that are water soluble and hence have enhanced bioavailabilityand improved processing characteristics for the preparation andformulation of drug compositions. Examples of suitable salts aretartrate, citrate, fumarate, maleate, maliate, phosphate, succinate,sulphate, and edisylate.

It was found that a hemi-tartrate ofN-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamideis particularly suitable. Accordingly, one embodiment providesN-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl carbamide hemi-tartrate (pimavanserin tartrate) accordingto the formula IV,

Accordingly, some embodiments disclosed herein relate to preparing acompound of formula IV (pimavanserin tartrate) by the methods describedherein.

The compound of formula IV may be prepared as an integrated part of theprocess for synthesizing the compound of formula I as described above byusing tartaric acid as the salt forming acid. Alternatively, thetartrate salt may be formed by reaction of the isolated compound offormula I with tartaric acid.

In one embodiment,N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethylcarbamide hemi-tartrate is formed by adding tartaric acid tothe compound of formula I, and isolating the hemi-tartrate of thecompound of formula I. The hemi-tartrate may be isolated throughprecipitation by cooling, solvent removal, adding an anti-solvent, or acombination of these methods. In one embodiment, one or more solventsare added in one of the steps in the reaction that have a low solubilityfor the hemi-tartrate, such as isopropyl acetate, a ketone (such asacetone or 2-butanone or MEK), and/or tetrahydrofuran. The hemi-tartrateprecipitates and forms a suspension, which may be stirred for up to 3days before filtering off the solid from the reaction mixture preferablyat ambient conditions. The solid residue may be washed, and then driedat temperatures up to 50° C., if desired, under vacuum.

The hemi-tartrate of formula IV is obtained in high yields and purity.The mother liquors can be used to isolate more hemi-tartrate of formulaIV in the usual manner. The hemi-tartrate may be further purified byconversion to the free base of formula I and isolating a solution of thebase, which is then used to re-precipitate the hemi-tartrate by theaddition of tartaric acid.

In some embodiments pimavanserin tartrate is obtained in a purity of atleast 96%, e.g. at least 98% based on HPLC (high performance liquidchromatography). A suitable HPLC method is for example using a Waterssystem such as Waters alliance LC-System/Agilent 1100, 1200, 1260 and adetector 2487, PDA (2996)/DAD, VWD. A suitable column is Waters XBridgeC18, 15 cm×4.6 mm, 5 μm. A, or equivalent, suitable test solution can bea 100 μg/ml solution containing the sample dissolved in 50 vol % aqueoussolution (pH 9.0) (eluent A) and 50 vol % of a solution of acetonitrileand 20 vol % methanol (eluent B). Additional setup parameters may forexample be the following: Flow rate: 1.0 ml/min, Temperature of columnoven: 40° C., Temperature of auto sampler: 5° C., Wavelength: 210 nm. Amixture of eluent A (90 vol %) and eluent B (10 vol %) may for examplebe used. As a standard pimavanserin tartrate (or polymorphic Form Cwhichever is appropriate) may be used. The purity may be directlyobtained from the software accompanying the equipment.

In some embodiments, the hemi-tartrate of the compound of formula I isobtained by reaction with tartaric acid where both reagents aredissolved in ethanol. It was surprisingly discovered that efficientremoval of impurities can be obtained by precipitation of the tartratefrom ethanol.

Pimavanserin tartrate can be obtained in many polymorphic forms asdescribed in WO2006/037043. For example, the procedure described usingMEK generates polymorph C of pimavanserin. Polymorphic Form C has beenfound to be a thermostabile form of pimavanserin and is for examplecharacterized by having an endotherm with an onset of between 167 and177 C.° as obtained by differential scanning calorimetry (DSC) inaccordance with USP <891>. The DSC was obtained using a Mettler-Toledo822, using a 4-6 mg sample and 40 μl aluminium crucible with a lid andpin hole. The analysis is performed under nitrogen (10 ml/min) at aheating rate of 10° C./min between 80° C.-210° C. Optionally polymorphicForm C may be characterized by powder diffraction (pXRD), see FIG. 4 ofWO2006/037043.

In some embodiments polymorphic Form C is obtained in a purity of atleast 98%, e.g. at least 99% based on HPLC, for example using the methoddescribed hereinabove.

In some embodiments polymorphic Form C is obtained through directformation from pimavanserin (as defined in Formula (I). Hence there isno need of isolating and purifying pimavanserin, or pimavanserintartrate, as it is possible to form polymorphic Form C directly. It ispossible to obtain polymorphic Form C in a purity of at least 96%, suchas at least 98%, such as at least 99% via the direct formation frompimavanserin. Obtaining polymorphic Form C via direct formation frompimavanserin is considered a benefit of the process disclosed herein.

Stability and Pharmaceutical Formulations

As mentioned above, the pimavanserin and pimavanserin tartrate are eachsuitable as an active pharmaceutical ingredient (API) or pro-drug inpharmaceutical formulations to inhibit an activity of a monoaminereceptor, preferably a serotonin receptor of the 5-HT2A subclass.Pimavanserin tartrate has very good solubility in aqueous systems andthe free base is deliberated at physiological pH ranges, providing ahigh bioavailability. Pimavanserin tartrate possesses high storagestability.

The amount of pimavanserin tartrate required in a formulationsubstantially depends on type of formulation and desired dosages duringadministration time periods. The amount in an oral formulation may befrom 0.1 to 500 mg, preferably from 0.5 to 300 mg, and more preferablyfrom 1 to 100 mg, such as 10 to 60 such as 20 to 40 mg. Oralformulations may be solid formulations such as capsules, tablets, pillsand troches, or liquid formulations such as aqueous suspensions, elixirsand syrups. Solid and liquid formulations also encompass incorporationof the compound of formula IV into liquid or solid food. Liquids alsoencompass solutions of pimavanserin tartrate for parenteral applicationssuch as infusion or injection.

Pimavanserin may be formulated as a powder (e.g., micronized particles),granules, suspensions or solutions, or may be combined together withother pharmaceutically acceptable ingredients in admixing the componentsand optionally finely dividing them, and then filling capsules, composedfor example from hard or soft gelatine, compressing tablets, pills ortroches, or suspending or dissolving them in carriers for suspensions,elixirs and syrups. Coatings may be applied after compression to formpills.

Pharmaceutically acceptable ingredients are well known for the varioustypes of formulations and may be for example binders such as natural orsynthetic polymers, excipients, lubricants, surfactants, sweetening andflavouring agents, coating materials, preservatives, dyes, thickeners,adjuvants, antimicrobial agents, antioxidants and carriers for thevarious formulation types.

Examples for binders are gum tragacanth, acacia, starch, gelatine, andbiological degradable polymers such as homo- or co-polyesters ofdicarboxylic acids, alkylene glycols, polyalkylene glycols and/oraliphatic hydroxyl carboxylic acids; homo- or co-polyamides ofdicarboxylic acids, alkylene di amines, and/or aliphatic aminocarboxylic acids; corresponding polyester-polyamide-co-polymers,polyanhydrides, polyorthoesters, polyphosphazene and polycarbonates. Thebiological degradable polymers may be linear, branched or crosslinked.Specific examples are poly-glycolic acid, poly-lactic acid, andpoly-d,l-lactide/glycolide. Other examples for polymers arewater-soluble polymers such as polyoxaalkylenes (e.g., polyoxaethylene,polyoxapropylene and mixed polymers thereof), poly-acrylamides andhydroxylalkylated polyacrylamides, poly-maleic acid and esters or-amides thereof, poly-acrylic acid and esters or -amides thereof,poly-vinylalcohol and esters or -ethers thereof, poly-vinylimidazole,poly-vinylpyrrolidon, and natural polymers like chitosan.

Examples for excipients are phosphates such as dicalcium phosphate.

Examples for lubricants are natural or synthetic oils, fats, waxes, orfatty acid salts like magnesium stearate.

Surfactants may be anionic, cationic, amphoteric, or neutral. Examplesfor surfactants are lecithin, phospholipids, octyl sulfate, decylsulfate, dodecyl sulfate, tetradecyl sulfate, hexadecyl sulfate andoctadecyl sulfate, sodium oleate or sodium caprate,1-acylaminoethane-2-sulfonic acids, such as1-octanoylaminoethane-2-sulfonic acid, 1-decanoylaminoethane-2-sulfonicacid, 1-dodecanoylaminoethane-2-sulfonic acid,1-tetradecanoylaminoethane-2-sulfonic acid,1-hexadecanoylaminoethane-2-sulfonic acid, and1-octadecanoylaminoethane-2-sulfonic acid, and taurocholic acid andtaurodeoxycholic acid, bile acids and their salts, such as cholic acid,deoxycholic acid and sodium glycocholates, sodium caprate or sodiumlaurate, sodium oleate, sodium lauryl sulphate, sodium cetyl sulphate,sulfated castor oil and sodium dioctylsulfosuccinate,cocamidopropylbetaine and laurylbetaine, fatty alcohols, cholesterols,glycerol mono- or di-stearate, glycerol mono- or di-oleate and glycerolmono- or di-palmitate, and polyoxyethylene stearate.

Examples for sweetening agents are sucrose, fructose, lactose oraspartam.

Examples for flavouring agents are peppermint, oil of wintergreen orfruit flavours like cherry or orange flavour.

Examples for coating materials are gelatine, wax, shellac, sugar orbiological degradable polymers.

Examples for preservatives are methyl or propylparabens, sorbic acid,chlorobutanol, phenol and thimerosal.

Examples for adjuvants are fragrances.

Examples for thickeners are synthetic polymers, fatty acids and fattyacid salts and esters and fatty alcohols.

Examples for antioxidants are vitamins, such as vitamin A, vitamin C,vitamin D or vitamin E, vegetable extracts or fish oils.

Examples for liquid carriers are water, alcohols such as ethanol,glycerol, propylene glycol, liquid polyethylene glycols, triacetin andoils. Examples for solid carriers are talc, clay, microcrystallinecellulose, silica, alumina and the like.

The pharmaceutical formulation may also contain isotonic agents, such assugars, buffers or sodium chloride.

Pimavanserin or pimavanserin tartrate may also be formulated aseffervescent tablet or powder, which disintegrates in an aqueousenvironment to provide a drinking solution.

A syrup or elixir may contain the pimavanserin or pimavanserin tartrate,sucrose or fructose as sweetening agent, a preservative likemethylparaben, a dye, and a flavouring agent.

Slow release formulations may also be prepared from the compound ofpimavanserin or pimavanserin tartrate in order to achieve a controlledrelease of the active agent in contact with the body fluids in thegastro intestinal tract, and to provide a substantial constant andeffective level of the active agent in the blood plasma. Pimavanserin orpimavanserin tartrate may be embedded for this purpose in a polymermatrix of a biological degradable polymer, a water-soluble polymer or amixture of both, and optionally suitable surfactants. Embedding can meanin this context the incorporation of micro-particles in a matrix ofpolymers. Controlled release formulations are also obtained throughencapsulation of dispersed micro-particles or emulsified micro-dropletsvia known dispersion or emulsion coating technologies.

Pimavanserin or pimavanserin tartrate is also useful for administering acombination of therapeutic effective agents to an animal. Such acombination therapy can be carried out in using at least one furthertherapeutic agent which can be additionally dispersed or dissolved in aformulation. The pimavanserin or pimavanserin tartrate and itsformulations respectively can be also administered in combination withother therapeutic agents that are effective to treat a given conditionto provide a combination therapy

One embodiment is a method of delivering pimavanserin to a host,comprising administering to the host an effective amount ofpimavanserin. A further embodiment is the use of the pimavanserin orpimavanserin tartrate for the manufacture of a medicament useful in theinhibition of an activity of a monoamine receptor, preferably aserotonin receptor of the 5-HT2A subclass.

EXAMPLES Experimental Procedures and Instrumentation

Examples of instrumentation and methods used to assist in thepreparation of compounds described herein are:

NMR Equipment: VARIAN INOVA 400 mhz.

GC-MS Equipment: TRACE GC THERMO FINNIGAN (Method: Column: ZB-SMS,30×0.25 mm, 0.25 μm. Temp gradient: 50° C. for 2 min then to 320° C. at20° C./min. Hold time: 15 min. Flow: 1.0 ml/min, Split: 1:50, Inj.Temp.: 200° C. Injection vol: 1 μL Diluent: Acetonitrile).

LC-MS Equipment: AGILENT 6530 ACCURATE-MASS Q-TOF (Method: Column:ACQUITY UPLC BEH C18, 100×2.1 mm, 1.7 μm. Eluent A: 0.1% HFo inAcetonitrile. Eluent B 0.1% HFo in H₂O. Gradient 10% A 90% B at 0 min,95% A 5% B at 15 min, 95% A 5% B at 20 min. Flow: 0.25 ml/min, Temp: 40°C. Injection vol: 1 μL. Diluent: Acetonitrile.); or LCQ ADVANTAGE THERMOFINNIGAN (Method: Column:

Symmetry Shield RP18, 150×3.0 mm, 3.5 μm, Eluent A: 0.05% TFA inAcetonitrile. Eluent B 0.058% TFA in H2O. Gradient 5% a 95% B at 0 min,95% A 5% B at 30 min, 95% A 5% B at 36 min, 5% a 95% B at 36.5 min, 5% a95% B at 42 min. Flow: 0.6 ml/min, Temp. 40° C. Injection vol: 4 μL.Diluent: Acetonitrile).

HPLC Equipment: WATERS 2695 (Method: Column: WATER XBRIDGE C18, 5 μm,150 mm*4.6 mm. Eluent A: pH 9.0 Ammonium (50 mM) Buffer, Eluent B:Acetonitrile:Methanol 1:1. Gradient: 10% B at 0 min, 100% B at 30 min,10% B at 30.1 min, 10% Bat 36 min. Flow: 1 ml/min, Temp. 40° C.Injection vol: 20 μL. Diluent: Acetonitrile:H₂O (8:2)).

Unless Otherwise Stated, Starting Materials were Obtained fromCommercial Sources Such as (but not Limited to) Sigma-Aldrich and Acros.

Example 1a: Preparation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine(Starting Material 1 (SM1)

Sodium triacetoxyborohydride (6.5 kg) was added over 1.5 h to a solutionof N-methylpiperid-4-one (3.17 kg) and 4-fluorobenzylamine (3.50 kg) inmethanol (30 L) maintaining the temperature under 27° C. The reactionmixture was stirred for 15-24 h at 20-40° C. The residual amine waschecked by HPLC gel chromatography (4-fluorobenzylamine: <5%). Asolution of 30% sodium hydroxide (12.1 kg) in water (15-18 kg) was addedover 1-2 h maintaining the temperature under 20-30° C. Methanol wasdistilled off to a residual volume of 26 liters. Ethyl acetate was added(26 L), the solution was stirred for 15-30 min, the phases wereseparated over 15-20 min and the lower aqueous phase was discarded.Ethyl acetate was distilled under reduced pressure from the organicphase at 70-80° C. At this stage the residue was mixed with a secondcrude batch prepared according to this method. The combined productswere then distilled at 139-140° C./20 mbar to yield 11.2 kg product(>82%).

Example 1b: Scaled-Up Preparation of SM1

The reaction step was performed in three batches, which were eachmanufactured on the same scale as described below and the resultingproducts combined for further use in the next step.

N-Methylpiperidone (33.0 kg) and 4-fluorobenzylamine (35.4 kg) weredissolved in methanol (220.1 kg) at 15-19° C. (exothermic dissolution),and a suspension of 5% palladium on charcoal (1.2-1.3 kg) in methanol(17-18 kg) was added under nitrogen and the line rinsed with methanol(5.6 kg). The bulk was heated to 20-30° C. and hydrogenated at the sametemperature and ˜5 bar until the hydrogen absorption stopped (˜12 h).The residual starting material was checked by GC, and the bulk wasclarified on a Lens filter equipped with a thin CELTROX pad and 2×G92filter papers. The line was rinsed with methanol (9.8 kg). The solventwas distilled under reduced pressure (265-60 mbar; 35-40° C.) and theoily residue was purified by fractional distillation under vacuum at˜135-140° C. at 8-0.5 mbar. Impure fractions of the three batches werecombined and redistilled.

Total yield (combined three batches and redistilled fractions): 147.4 kg(78.1%).

Example 2a: Preparation of (4-isobutoxyphenyl)methanamine (StartingMaterial 2 (SM2))

Preparation of

4-Hydroxybenzaldehyde (4.0 kg) and ethanol (20 L) were added to asolution of isobutyl bromide (9.0-10 kg) in ethanol (15-18 L). Potassiumcarbonate (13-14 kg) was added and the suspension was refluxed (74-78°C.) for 5 days. The residual 4-hydroxybenzaldehyde was checked by HPLC(<10%). The suspension was cooled to 20° C. and used in the next step.

Preparation of

Hydroxylamine (50% in water, 8-9 kg) was added to the aldehyde(4-isobutoxybenzaldehyde) obtained in the previous step (174 L, 176 kg)and ethanol (54 L). The suspension was refluxed (77° C.) for 3-5 h.Unreacted residual aldehyde was checked by HPLC (<5%). The suspensionwas cooled to 30° C., filtered and the filter was washed with ethanol(54 L). The solution was concentrated by distillation under reducedpressure at 30° C. to a residual volume of 65-70 liters. The solutionwas cooled to 25° C. and water (110 L) was added. The suspension wasconcentrated by distillation under reduced pressure at 30° C. to aresidual volume of 100-105 liters. Petroleum ether (60-90 fraction,90-100 L) was added and the mixture was heated to reflux (70-80° C.).The solution was cooled to 40° C. and crystallization was initiated byseeding. The suspension was cooled to 0-5° C. and stirred for 3-6 h. Theproduct was centrifuged and the cake was washed with petroleum ether(60-90 fraction, 32 L). The wet cake was dried at about 40° C. to yield15-18 kg product (60-70%) used in the next step.

Preparation of

The product from the previous step (15.7 kg) was dissolved in ethanol(120-130 L). Acetic acid (8.0-9.0 kg) and palladium on charcoal 5% wet(1.0-1.5 kg) were added. The oxime was hydrogenated at 22° C. and 1.5bar for 3-6 h. Consumption of oxime was checked by HPLC. The catalystwas filtered and the solvent was distilled under reduced pressure at 36°C. to a final volume of 30-32 L. Ethyl acetate (60-70 L) was added andthe mixture was heated to reflux (75° C.) until dissolution. Thesolution was cooled to 40-50° C. and the crystallization was initiatedby seeding. The suspension was cooled to 0-10° C. and stirred for 2-4 h.The product was centrifuged and the cake was washed with 2 portions ofethyl acetate (2×0.8 L). The wet cake was dried at a temperature ofabout 40° C. to yield 8-9 kg (40-50%). The obtained material is treatedwith sodium hydroxide in toluene to generate about quantitative yield ofSM2.

Example 2b: Alternative Preparation of SM2 Preparation of

The reaction step was performed in two batches. 4-Hydroxybenzaldehyde(141 kg) was dissolved in dimethylformamide (335 kg) at 15-25° C., thensolid potassium carbonate (320-330 kg) and potassium iodide (19-20 kg)were added portion wise at <30° C. and the suspension was heated up to70-90° C. The temperature of the condenser was fixed to 0-10° C. andisobutylbromide (315-320 kg) was added to the suspension over 4-6 h at75-90° C. At the end of the addition, the mixture was stirred for 2-4 hat 75-90° C. and residual starting material was checked by HPLC. Thesuspension was cooled to 20-30° C., diluted with 100% ethanol (500-550kg, denatured with isopropanol), stirred for 15-30 min at 20-30° C. andcentrifuged (3 loadings) to remove the excess of carbonate and potassiumbromide. The line and the cake were washed with 100% ethanol (2×32kg/loading). The solution is used as such in the next step.

Example 2c: Preparation of SM3

To the aldehyde solution resulting from Step b, 50% hydroxylamine inwater (110-120 kg) was added at room temperature over ˜0.5 h (theaddition is slightly exothermic), the line washed with ethanol (8-10kg), then the bulk was heated up to 70-77° C. and stirred at thistemperature for 2-4 h. The bulk was concentrated under reduced pressure(250-120 mbar, 45-55° C.) to ˜850-900 L, the residue quenched with water(900-1000 kg) at 45-55° C. and the residual ethanol distilled undervacuum (270-150 mbar, 45-55° C., residual volume=1466 L). The bulk wasdiluted with petrol ether 60-90 (500-600 kg) and heated at reflux (˜60°C.) to reach complete dissolution (˜20 min, visual check). The solutionwas cooled down to 5-15° C. (crystallization occurs at T=˜25-30° C.)over ˜5-6 h. After 1-2 h stirring at 10° C., the mixture was cooled to0-5° C. and stirred at this temperature for 2-4 h. The bulk wascentrifuged (3 loadings) and the cake washed with petroleum ether (2×23kg/loading), then dried under reduced pressure at 40° C. to afford thecrude oxime (210-215 kg).

Recrystallization:

The crude product (212 kg) was dissolved in hexane (640-650 kg) at15-25° C. and the suspension heated up to ˜60-70° C. Charcoal (6-10 kg)in hexane (26-30 kg) was added and the suspension was stirred for0.5-1.5 h. After filtration (the filter was washed with 30-40 kghexane), the solution was cooled to crystallisation temperature (˜50-60°C.), and the mixture was stirred for 1-2 h at this temperature. Thesuspension was cooled to 10-15° C. After stirring for ˜2-4 h at thattemperature, the bulk was centrifuged (3 loadings) and the cake washedwith cold hexane (2×13 kg/loading), then dried under reduced pressure at40° C.

Yield oxime: 190-200 kg (80-90% over the two steps)

Example 2d: Preparation of 4-iso-butyloxybenzylammonium acetate

The oxime (198 kg) from Step c was dissolved in ethanol (1140-1150 kg,denatured with isopropanol). Raney nickel catalyst (25-30 kg) was washedwith ethanol (690-700 kg) until the water content by Karl Fischer wasbelow 3000 ppm, then the anhydrous Raney-Nickel was added under nitrogento the oxime solution, the line washed with ethanol (62 kg) and thesuspension cooled down to 0-10° C. Ammonia gas (220-230 kg) was addedunder vacuum over ˜5-7 h (the addition is exothermic). Then thesuspension was heated to 40-50° C. The internal pressure increased to˜3-5 bar. The bulk was hydrogenated at 40-50° C. and 3-5 bar until thehydrogen absorption stopped (˜6-10 h) and the end of reaction waschecked by HPLC. The suspension was cooled to 10-20° C., the excess ofammonia was removed, and the bulk clarified by filtration over Celtrox(4-5 kg). The line was washed with ethanol (317 kg). The solvent wasdistilled under reduced pressure (150-10 mbar, 40-50° C.) and theresidue dissolved in toluene (700-800 kg) at ˜40° C. The solution wastransferred to a new reactor (previous reactor washed with 50-60 kgtoluene), and cooled to 20-30° C. Acetic acid (AcOH, 60-70 kg) wasslowly added (exothermic reaction) at 20-30° C. and the bulk heatedduring 20-40 min to ˜90-100° C. until complete dissolution was reached.The solution was cooled rapidly to 70-80° C. and seeded with aminoacetate product (50 g). The suspension was stirred at thecrystallization temperature for 30-60 min, cooled to 0-10° C. andstirred for ˜1-2 h at this temperature. The bulk was centrifuged (3loadings) and the cake washed with cold toluene (2×48 L/loading) andfinally dried under vacuum at (9-16 mbar) at ˜50° C. for 28 h.

Yield: 200-210 kg (80-90%)

Example 2e: Alternative Preparation of SM2 (4-iso-butyloxybenzylamine)

A solution of the aminoacetate (269 kg) from Step c in water (400-500kg) was basified with 30% sodium hydroxide solution (300-310 kg) to pH14 at 20-25° C. Then the amino base product was extracted with toluene(900-1000 kg) at 40-50° C. by stirring for 15-30 min. The bulk wasdecanted during 15-30 min at 40-50° C.; if necessary the pH was adjustedto >12 with additional 30% NaOH, then the layers were separated. Theorganic layer was washed with water (359 kg), then concentrated undervacuum (200-20 mbar) at 45-50° C. to give the aminobase as an oilyresidue.

Example 2f: Alternatively 4-iso-butyloxybenzylamine (SM2) and4-iso-butyloxybenzylamine acetate (SM2b) are Prepared According toFollowing Scheme

To potassium tertbutoxide (KOtBu, 1.4 eq, 77.7 g) 350-400 ml methyltert-butylether (MTBE) were added under a nitrogren atmosphere. Themixture was stirred at ambient temperature and isobutanol (1.6-2.00 eq,59-74.2 g) was added during 2 h while keeping a temperature of about50-60° C., and thereafter heated for about 1 h at about 50-60° C. Asolution of 4-fluorobenzonitrile (1 eq, 60 g) in about 60-80 ml MTBEunder anitrogen atmosphere were added dropwise to the reactor containingthe KOtBu while a temperature of less than about 55-60° C. wasmaintained, and thereafter the mixture kept at about 50-60° C. for about1-2 h. The mixture was cooled to about 10-15° C. and 200 ml water addedwhile a temperature of about less than 20° C. was maintained. Themixture was allowed to settle and phase separation occurred, and theaqueous phase separated. The organic phase was washed with water (2×120ml) and the solvent distilled off. Thereafter 300-400 ml of methanol wasadded to the residue at ambient temperature, and the mixture transferredto an autoclave. Acetic acid (0.8 eq-1.2 eq, 23.8-35.7 g) and palladium(Pd) catalyst type JM 39 5.5 w % Pd WNASS (0.001 eq-0.01 eq, 2.1-21.0 g)(commercially available from Johnson and Matthey) were added undernitrogen washing together with methanol (15-20 ml). The mixture washeated to about 45-50° C. and hydrogenated at 1-5 bar H₂ for 3-8 h andthereafter allowed to cool to ambient temperature. The mixture wasfiltered and the solvent was removed and the remaining residue washedwith toluene, and the product dried to give SM2b.

Example 2g: Alternatively 4-iso-butyloxybenzylamine (SM2) and4-iso-butyloxybenzylamine acetate (SM2b) are Prepared According toFollowing Scheme

KOH (1.36 g, 24.2 mmol, 3 eq) was dissolved in water (1.4 ml) and addedto the solution of 4-fluorobenzaldehyde (1.0 g, 8.1 mmol, 1 eq).Isobutanol (0.66 g, 8.9 mmol, 1.1 eq) and tetrabutyl ammoniumhydrogensulfate (TBAH, 0.27 g) in toluene (7 ml). The reaction mixturewas vigorously stirred at 50-52° C. overnight and thereafter dilutedwith water (5 ml), dried and concentrated in vacuo to give 0.877 g ofcrude product. The crude product was purified by column chromatographyusing ethyl acetate: heptane to give 0.6 g of 4-isobutoxy benzaldehyde.4-Isobutoxy benzaldehyde can thereafter be converted to SM2 and SM2brespectively using the procedure outline in example 2b.

Example 2i: Alternatively 4-iso-butyloxybenzylamine (SM2) and4-iso-butyloxybenzylamine acetate (SM2b) are Prepared According toFollowing Scheme

To 60% sodium hydride in mineral oil (24.8 g-33.00, 1.5 eq-2.0 eq)suspended in THF (450-500 ml), heated to 50-60° C. isobutanol (45.9g-61.2 g, 1.5 eq-2.0 eq) was added over 30-60 min and thereafter stirredfor 1 h. 4-Fluorobenzonitrile (50 g, 1 eq) in THF (30 ml) was added over1-2 h followed by stirring for about 2-3 h. The mixture was cooled toroom temperature and brine (10%, 300 ml) was added. The reaction mixturewas extracted with MTBE (300 g), organic layer was separated, washedwith water (100 ml), and evaporated to give 4-isobutoxybenxonitrile.

Alternatively potassium tert-butoxide (KOtBu, 55.5 g-92.5, 1.2-2.0 eq)was suspended in MTBE (250-300 ml) and heated to 50-60° C. Isobutanol(36.3-63.0 g, 1.2-2.0 eq) was added over about 30-60 min. After 1 h asolution of 4-fluorobenzonitrile (50 g, 1 eq) in MTBE (50 ml) was addedover about 1 h and the flask was washed with MTBE (10 ml). The mixturewas stirred overnight (about 12-18 h) at a temperature of 50-60° C. andthereafter cooled to room temperature and followed by addition ofdeionized water (200 ml). The layers were separated and solvent (200 g)distilled off from the organic layer under vacuum. MeOH (310-350 ml) wasadded and solvent (100-150 g) distilled off under vacuum to give asolution, which was diluted with aqueous ammonium chloride (NH₄Cl) andextracted with ethyl acetate. The separated organic layer was dried oversodium sulphate, filtered and concentrated to afford crude product whichupon column chromatography afforded pure 4-isobutoxybenzonitrile as anoil.

To 4-isobutoxybenzonitrile as obtained by any of the described methods(20 g, 1 eq) dissolved in MeOH (75 ml), aqueous 25% NH₃ (25.4 g, 3 eq)and wet activated Raney-Nickel (about 3 g) were added. The mixture washydrogenated at 4-5 bar and 50° C. for 5 h. and thereafter cooled to RTand the catalyst filtered off. The solvent (about 70 g) was distilledoff, followed by dilution with toluene (150 ml), which gave separatedlayers. About 50 ml solvent was distilled off at 50° C. from the organiclayer and acetic acid (AcOH, 4.7-7.8 ml, 0.8 eq-1.2 eq) was added over15-30 min at 50° C. The resulting suspension was cooled to about 20° C.and stirred for 2-4 h and thereafter filtered and washed using toluene(10-20 ml). Evaporation at 40° C., <50 mbar, during 12 h gave the4-iso-butyloxybenzylamine acetate (SM2b) as a white powder in about70-80% yield. The product was determined to have a high performanceliquid chromatography (HPLC) purity of about 99.5%.

Example 3a: Preparation of Pimavanserin Via Activation of DimethylCarbonate (DMC)

Route 1: SM2 (179 mg, 1.00 mmol) and catalyst(Zr(O^(t)Bu)₄/2-hydroxypyridine 0.10 equiv.) were added to DMC (99.0 mg,1.1 equiv.). Zr(O^(t)Bu)₄ is short for zirconium tetra tertiarybutoxide. The mixture stirred for about 12 h at 80° C. followed byaddition of SM1 (1.10 equiv.) and catalyst (0.10 equiv.). The mixturewas stirred at 120° C. for about 24 h. Yield: 22% pimavanserin

Route 2: was performed in accordance with route 1 replacing the route 1catalyst by Sodium tert-butoxide (NaO^(t)Bu, or optionally potassiumtert-butoxide)) and stirred at 120° C. for about 72 h. Yield: 20%pimavanserin. Optionally Route 2 was performed using 18-crown-6 asco-catalyst (0.1 equiv.). The crown ether was added to SM1 dissolved indissolved in toluene (0.3 ml, 2M). Yield: 47% pimavanserin.

Optionally I1 may be isolated, and has for example been isolated fromroute 1 in about 81% yield. I1 was characterized by NMR: δ_(H) (400 MHz,dmso-d6) 7.58 (t, J=6.2 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6Hz, 2H), 4.09 (d, J=6.2 Hz, 2H), 3.70 (d, J=6.5 Hz, 2H), 3.53 (s, 3H),2.04-1.94 (m, 1H), 0.96 (d, J=6.7 Hz, 6H).

Example 3b: Preparation of Pimavanserin Via Activation ofDimethylcarbonate (DMC)

SM1 (222 mg, 1.00 mmol) and catalyst (Zr(O^(t)Bu)₄/2-hydroxypyridine0.10 equiv.) were added to DMC (99.1 mg, 1.10 equiv.). The mixture wasstirred for about 25 h at 50-100° C. followed by addition of SM2 (1.10equiv.) and co-catalyst (0.10 equiv.). The mixture was stirred at 100°C. for about 25 h to give pimavanserin.

Example 3c: Preparation of Pimavanserin Using Diphenyl Carbonate

Diphenyl carbonate (14.9-20.31 g, 1.1-1.5 eq) in toluene (35-50 ml) wasstirred and heated to about 35° C. until a solution was formed. SM2(11.3 g) in toluene (about 90 ml) was added over 3 h at a temperature ofabout 30-40° C. The mixture was maintained at about 30-40° C. for about14-24 h in order to give phenyl (4-isobutoxybenzyl)carbamate (I1.1) in99%, and some amounts of SM2 (less than 1.0 a %) (checked by HPLC).

The mixture was cooled to 0° C. and sodium hydroxide (2.25 g) indeionized water (40 g) was added, and the temperature kept below 10° C.Upon completed addition the mixture was stirred and thereafter allowedto settle and the aqueous layer was removed. The organic layer washeated to about 40° C., and hydrochloric acid (0.5 vol %, about 50 ml)was added, and thereafter the mixture maintained for about 10 min beforesettling for 15 min. The aqueous layer was removed and the organic layerwashed with deionized water (20 g), stirred and maintained at about 40°C. before settling for 15 min. Again the aqueous layer was removed andthe solvent distilled off from the organic layer under vacuum. Theobtained residue was washed with 95/5 (w %/w %) heptane and ethylacetate. The mixture was maintained at an elevated temperature (about50° C.) before cooling the resulting suspension to 0-10° C. Thesuspension was maintained for 3-5 h before obtaining I1.1 by filtration.The crude 11.1 was washed with heptane and dried to provide 17.8 g (95%)I1.1.

¹H NMR of I1.1 (CDCl₃): δ 1.0 (d, 6H), 2.1 (m, 2H), 3.7 (d, 2H), 4.3 (d,2H), 5.2 (b, 1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (m, 1H), 7.22 (m, 2H),7.8 (m, 3H);

Pimavanserin is obtained as described in examples 4e, 4f, and 4g.

Example 3d: Preparation of Pimavanserin Using Diphenyl Carbonate

SM2 was added over 10 min to a mixture of diphenyl carbonate (DPC,1.1-1.5 eq) in toluene (20 eq). The mixture was maintained at roomtemperature for about 3-5 h in order to give phenyl(4-fluorobenzyl)(1-methylpiperidin-4-yl)carbamate (I2.1) in 98%, andsome amounts of 1,3-bis(4-isobutoxybenzyl)urea. To the mixture potassiumcarbonate (0.5-1.0 eq) and SM1 (1 eq) were added and heated to 65-80° C.for 5 h followed by cooling to 50° C. and addition of sodium hydroxide(1.1 eq) in water, followed by additional water. The organic layer wasseparated and solvent was distilled off and heptane:ethyl acetate (95:5)was slowly added followed by cooling to room temperature, maintained atabout 3 h and thereafter filter washed with heptane:ethyl acetate (95:5)to give pimavanserin in a yield of about 90% and about 99% purity. ¹HNMR (CDCl₃) of 12.1: δ 1.6-2.0 (m, 6H); 2.2 (s, 3H); 2.8 (m, 2H); 4.0(br m, 1H); 4.5 (br s, 2H), 7.0-7.40 (m, 9H).

The step to obtain pimavanserin can be carried out analogous to theprocedures described in examples 4e, 4f, and 4g.

Example 4a: Preparation of Pimavanserin Using Methyl Chloroformate

Methyl chloroformate (0.538 ml, 7.00 mmol) was added dropwise to astirred solution of N-(4-fluorophenylmethyl)-1-methylpiperidin-4-amineSM1 (1.11 g, 5.00 mmol) and triethylamine (0.842 ml, 6.00 mmol) indichloromethane (20 ml). After 48 h, LCMS analysis indicated fullconsumption of starting materials. A 5 ml aliquot of the reactionmixture was washed with ice-cold sat. aq. NaHCO₃ (5 ml) and water (2×5ml), dried (Na₂SO₄) and concentrated under reduced pressure. The cruderesidue was purified by chromatography on silica gel (1:19methanol/dichloromethane) to give methyl(4-fluorophenylmethyl)(1-methylpiperidin-4-yl)carbamate (I2) (43 mg,11%) as a colourless syrup; δ_(H) (400 MHz, dmso-d6) 7.28-7.24 (m, 2H),7.15-7.10 (m, 2H), 4.39 (s, 2H), 3.73 (br s, 1H), 3.62 (br s, 3H),2.75-2.70 (m, 2H), 2.09 (s, 3H), 1.83 (td, J=11.7, 2.3 Hz, 2H), 1.63(qd, J=12.1, 3.9 Hz, 2H), 1.49-1.38 (m, 2H); 6c (100 MHz, dmso-d6)161.0, 156.2, 136.0, 128.6, 115.0, 54.8, 54.2, 52.4, 45.6, 45.5, 29.5;LCMS m/z 281.0 (M+H), 109.5, 98.1.

Intermediate I2 was used to obtained pimavanserin as described inExample 4a.

Example 4b: Preparation of Pimavanserin Using Methyl Chloroformate

Methyl (4-isobutoxybenzyl)carbamate was prepared by adding methylchloroformate (about 1 eq) to SM2 (1 eq) in toluene during 5 h followedby heating at 40° C. followed by layer separation. The solvent wasdistilled off from the organic layer and heptane:ethyl acetate (95:5)was added slowly to give the methyl (4-isobutoxybenzyl)carbamate (I1)after filtering and washing. Yield: about 80%. ¹H NMR CDCl₃: δ 1.0 (d,6H); 2.0 (m, 1H); 3.7 (s, 3H); 4.28 (s, 3H); 4.3 (s, 2H); 4.9 (br, 1H);6.8 (d, 2H); 7.2 (d, 2H).

Methyl (4-isobutoxybenzyl)carbamate (1 eq) was added to methyl(4-fluorobenzyl)(1-methylpiperidin-4-yl)carbamate (SM1, 1 eq) in tolueneand triethylamine (1.5 eq) and heated to 110° C. for 20 h. Afterconventional phase separation work-up pimavanserin was obtained in about4-5% yield.

Example 4c: Preparation of Pimavanserin Using 2,2,2-trifluoroethylchloroformate and bis (2,2,2 trifluoroethyl) carbonate

2,2,2-trifluoroethyl (4-isobutoxybenzyl) carbamate was prepared bytreating SM2 with a mixture of bis (2,2,2 trifluoroethyl) carbonate and2,2,2-trifluoroethyl chloroformate (prepared as described in Tetrahedron67 (2011) 3619-3623) to obtain 2,2,2-trifluoroethyl (4-isobutoxybenzyl)carbamate in about 80% yield. SM2 (1.0 g, 6 mmol, 1 eq,) and the mixtureof bis (2,2,2 trifluoroethyl) carbonate and 2,2,2-trifluoroethylchloroformate (1.32 g, ˜6 mmol, ˜1 eq.) and DIPEA(N,N-diisopropylethylamine, 1 ml) in acetonitrile (3 ml) were heated at70-75° C. in a sealed tube for 2 h and allowed to cool to roomtemperature. Xylene (0.45 ml) was added to reaction mixture, which wasevaporated to dryness to give 1.66 g of 2,2,2-trifluoroethyl(4-isobutoxybenzyl) carbamate. The crude product was dissolved inacetonitrile (3 ml) and SM1 (1.49 g, 7 mmol, 1.2 eq.) and DBU(1,8-Diazabicyclo[5.4.0]undec-7-ene, 0.51 g, 0.5 eq.) added. The mixturewas heated at 70-75° C. in a sealed tube for 4 h and allowed to cool toroom temperature. Chloroform (10 ml) was added to the reaction mixtureand organic was washed with water (3×10 ml), dried and evaporated todryness to give 2.83 g of crude pimavanserin. After triturating thecrude product with n-heptane the purity increased to 70.5 area %. Yield:about 73%.

Example 4d: Preparation of Pimavanserin Using p-nitro-phenylChloroformate

Analogous to Examples 4b and 4c 4-nitrophenyl(4-isobutoxybenzyl)carbamate was prepared in a yield of about 80% andthereafter mixed with SM1 and converted to pimavanserin using aprocedure similar to the procedure described in Example 4b. Pimavanserinwas obtained in about 46% yield and the by-product1,3-bis(4-isobutoxybenzyl)urea was observed in substantive amounts.

¹H NMR (CDCl₃): δ 1 (d, 6H), 2.05 (m, 1H), 3.7 (d, 2H), 4.38 (d, 2H),5.35 (b, 1H), 6.88 (d, 2H), 7.24 (d, 2H), 7.30 (d, 2H), 8.22 (d, 2H).

Example 4e: Preparation of Pimavanserin Using Phenyl Chloroformate

A solution of 4-isobutoxybenzyl amine (1 g, 5.6 mmol, 1 eq) in THF ortoluene (5 ml) was added to a flask containing potassium carbonate (1.5eq) and phenyl chloroformate at room temperature and stirred for 1 h.The mixture was extracted with EtOAc (ethyl acetate), and the organiclayer washed with NH₄Cl solution followed by water, dried over sodiumsulfate and concentrated to afford pure product I1.1 as white solid(optionally I.1.1 may be isolated as described in the followingsection). Optionally I1.1 does not need to be isolated before next step.

Yield: 1.6 g 95%

Optionally I1.1 may be prepared by free-basing SM2b by dissolving SM2bin water and adding about 1 eq of potassium carbonate followed bytoluene and thereafter adding phenyl chloroformate over 5 h at atemperature of about 20° C. and optionally isolating I1.1 by heating to40° C. followed by layer separation, distillation of the organic phaseand slow addition of heptane:ethyl acetate (95:5) to give I1.1 afterfiltration and washing. Optionally, the free-basing of SM2b may be doneby sodium hydroxide as base.

¹H NMR of I1.1 (CDCl₃): δ 1.0 (d, 6H), 2.1 (m, 2H), 3.7 (d, 2H), 4.3 (d,2H), 5.2 (b, 1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (m, 1H), 7.22 (m, 2H),7.8 (m, 3H);

LC/MS of I1.1—Column: Symmetry Shield RP18, 150×3.0 mm, 3.5 μm, EluentA: 0.05% TFA in Acetonitrile. Eluent B 0.05% TFA in H2O. Gradient 5% a95% B at 0 min, 95% A 5% B at 30 min, 95% A 5% B at 36 min, 5% a 95% Bat 36.5 min, 5% a 95% B at 42 min. Flow: 0.6 ml/min, Temp. 40° C.Injection vol: 4 μL. Sample preparation 1-3 mg in 1 ml Acetonitrile.Retention time: 21.85 min, M+H⁺=299.78

To a toluene solution of phenyl 4-isobutoxybenzylcarbamate (I1.1) (0.2g, 0.67 mmol, 1 eq) and SM1 (0.15 g, 0.67 mmol, 1 eq) was added K₂CO₃(0.2 g, 1.34, 2 eq), and the mixture was heated at 90° C. for 24 h. Thereaction mixture was cooled to RT, washed with aq. NH₄Cl solution twiceto remove phenol, dried over sodium sulfate and concentrated to affordpimavanserin as white solid.

Yield: 0.26 g. 92%.

Example 4f: Scaled-Up Preparation of Pimavanserin Tartrate Via phenyl(4-isobutoxybenzyl)carbamate

I.1.1 (87 g, 1 eq) (prepared starting from 4-fluorobenzonitrile via SM2b(see example 2f and i) and further prepared in analogy with example 3cor 4e) and SM1 (54.7 g, 1 eq) in toluene (453 g) was heated to 65° C.for 5 h and thereafter cooled to 50° C. and washed with a solution ofsodium hydroxide (12.9 g, 1.1 eq) in water (348 g) followed by asolution of sodium hydroxide (6.4 g, 0.55 eq) in water (174 g), followedby 200 g water. Solvent was distilled off (about 300 g) andheptane:ethyl acetate (95:5) added slowly. The mixture was allowed tocool to room temperature (RT) during 1 h and thereafter stirred foranother 3 h before filtered washing with heptane:ethyl acetate (95:5).The obtained product was dried for 12 h at 50° C. to give pimavanserinas a white powder in a yield of about 94% and a HPLC purity of 99.8 a %,0.11 a % I1.1 and 0.07 a % 1,3-bis(4-isobutoxybenzyl)urea.

The obtained pimavanserin is thereafter converted into a tartrate salt,for example as described in Example 7.

Example 4g: Preparation of Pimavanserin Using Phenyl Chloroformate

A solution of SM1 (1 g, 4.5 mmol, 1 eq) in toluene (5 ml) was added to asolution of phenyl chloroformate (0.8 g, 5 mmol, 1.1 eq) and potassiumcarbonate (1.25 g, 9 mmol, 2 eq) in toluene (3 ml). The reaction mixturewas stirred for 1 h, then was washed with aqueous NH₄Cl solution. Thesolvent was evaporated to afford I2.1 as white solid. ¹H NMR (CDCl₃): δ1.6-2.0 (m, 6H); 2.2 (s, 3H); 2.8 (m, 2H); 4.0 (br m, 1H); 4.5 (br s,2H), 7.0-7.40 (m, 9H); Yield: 1.4 g, 95%

Pimavanserin is obtained by heating the solution of intermediate I2.1obtained above, with equivalent amount of SM2 in toluene in presence of2 eq of potassium carbonate, followed by work-up as described in theprevious examples.

Example 4h: Preparation of Pimavanserin Using dimethyl2,2′-(carbonylbis(oxy))dibenzoate (bis (methylsalicyl)-carbonate) asShown in the Following Scheme

A mixture of SM2 (0.27 g, 1.5 mmol, 1 eq) and bis(methylsalicyl)-carbonate (0.50 g, 1.5 mmol, 1 eq) in dichloromethane (2ml) was stirred at room temperature for 1.5 h to obtain carbamate 12.3.HPLC purity was 48%. The crude product was used as such for the nextstep and its yield estimated by HPLC as about 40% (area %).

The crude carbamate was dissolved in THF (4 ml) and SM1 (0.34 g, 1.5mmol, 1 eq) was added, the mixture was heated to 40-50° C. and stirredovernight. The solvent was evaporated to give crude product which waspurified by trituration with heptane (1 ml) to obtain 0.51 gpimavanserin in 65% purity (63% yield).

Alternatively, pimavanserin could also be prepared by reacting SM1 withbis (methyl salicyl) carbonate to give intermediate carbamate (I2.4) asshown in scheme. The intermediate carbamate was then treated with SM2 toobtain pimavanserin.

Alternatively salicyl chloro 2,2′-(carbonylbis(oxy))dibenzoic acid couldbe used instead of bis (methyl salicyl) carbonate.

Example 5a: Preparation of Pimavanserin Using Carbonyldiimidazole (CDI)Reaction Scheme:

N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (SM1, 120 mg) was treatedby sodium hydroxide to give the freebase which optionally is isolatedand thereafter added to CDT (excess such as 1.1-3 eq, such as 1.5-1.8eq) in toluene (2 ml). Optionally I4 can be isolated. Optionally methyliodide is used to convert 13 to 15 and thereafter the mixture wasstirred for about 1 h at room temperature (rt) followed by addition ofSM2b in toluene (about 1.1 eq.) and thereafter heated at 50° C. forabout 15 h. The reaction resulted in pimavanserin being obtained in aquantitative yield (using 1.8 eq CDI) aqueous work up.

Optionally SM2b may be treated with a suitable acid such as HCl,optionally isolated, and thereafter proceeding in accordance with theprocedure described. In order to obtain pimavanserin an additionaltrituration of crude pimavanserin was conducted.

Example 5b: Preparation of Pimavanserin Using Carbonyldiimidazole (CDI)

4-(2-Methylpropyloxy)-phenylmethylamine SM2 (822 mg, 4.59 mmol) wasadded in portions to a suspension of CDI (1.34 g, 8.25 mmol) in toluene(5 ml) at room temperature. The resulting mixture was stirred at roomtemperature for 4.5 h. The mixture was diluted with dichloromethane (45ml), washed with aqueous 1M NaOH (25 ml) and water (2×50 ml), dried(Na₂SO₄) and concentrated to giveN-(4-(2-methylpropyloxy)-phenylmethyl)imidazol-1-ylcarboxamide (I6)(1.20 g, 96%) as a colourless, amorphous powder; δ_(H) (400 MHz, CDCl₃)8.09 (s, 1H), 7.35 (s, 1H), 7.29-7.18 (m, 2H), 7.02 (s, 1H), 6.92-6.83(m, 2H), 6.52 (br s, 1H), 4.51 (d, J=5.4 Hz, 2H), 3.71 (d, J=6.5 Hz,2H), 2.14-2.01 (m, 1H), 1.02 (d, J=6.7 Hz, 6H); δ_(C) (100 MHz, CDCl₃)159.4, 148.9, 136.0, 130.6, 129.6, 128.8, 116.2, 115.1, 74.7, 44.7,28.4, 19.4; LCMS m/z 274.5 (M+H), 107.2, 69.1. I6 can then be broughtinto contact with SM1 to obtain pimavanserin.

Optionally 4-(2-Methylpropyloxy)-phenylmethylamine (SM2) (90.0 mg, 0.502mmol) was added in one portion to a suspension of CDI (146 mg, 0.900mmol) in toluene (2 ml) at room temperature. The resulting mixture wasstirred at room temperature for 1 h followed by addition ofN-(4-fluorophenylmethyl)-1-methylpiperidin-4-amine (SM1) (116 mg, 0.522mmol) and heating at 50° C. for 15 h. The mixture was diluted withdichloromethane (18 ml), washed with aqueous 1M NaOH (10 ml) and water(2×20 ml), dried (Na₂SO₄) and concentrated to give pimavanserin (206 mg,96%) as a colourless, amorphous powder.

Example 5c: Scaled-Up Preparation of Pimavanserin UsingCarbonyldiimidazole (CDI)

(4-isobutoxyphenyl)methanamine acetate (SM2b, 60 g, 1 eq) was dissolvedin water (96 ml) and aqueous 30% sodium hydroxide (75 ml) followed byaddition of toluene (300 ml). The mixture was heated to 55° C. and thelayers separated. Toluene (105 ml) was added to the organic layer andsolvent distilled off. THF (15 ml) was added and the solution cooled to20° C. The obtained solution was added at a temperature 20-30° C. to CDI(49.2-57.4 g, 1.2-1.4 eq) in toluene (195 ml) and thereafter maintainedfor about 1.5 h. The mixture was cooled to 10° C. and deionized water(120 ml) added slowly. The organic layer was collected and washed withanother portion of deionized water. The solvent (about 450-500 g) wasdistilled off and heptane:THF (9:1, 240 ml) added slowly. Theprecipitate was filter washed at 20° C. using heptane:THF (9:1, 60 ml).The obtained product I6 was obtained in about 89% yield and thereafterreacted with SM1 in analogy with the procedures described in Example 4f,and pimavanserin obtained in about 86% yield. Optionally I6 does notneed to be isolated but directly used in the next step.

The obtained pimavanserin is thereafter converted into a hemi-tartratesalt for example as described in Example 7.

Example 5d: Preparation of Pimavanserin Via Using di-tert-butylDicarbonate (Boc₂O)

Di-tert-butoxycarbonyl anhydride (Boc₂O, 1.46 g, 6.69 mol, 1.2 eq) wasdissolved in CH₃CN 10 ml and cooled to −10° C. Dimethylamino pyridine(DMAP, 0.14 g, 1.12 mol, 0.2 eq) was added and stirred for 10 min. After10 min 4-isobutoxybenzyl amine (SM2) in 10 ml CH₃CN added rinsing itwith CH₃CN (10 ml). The reaction was tirred for 15-30 min at −10° C. anddiluted with chloroform (50 ml). The reaction mixture was washed with 5%HCl aqueous solution, dried over MgSO4 and evaporated to dryness to givecrude product which was a mixture of the desired product4-isobutoxybenzyl isocyanate (60-70%), 20%N-tert-butoxycarbonyl-4-isobutoxybenzyamine and other minor by products.The crude product was not purified. The analysis is based on the 1H NMRof the crude product mixture. ¹H NMR (CDCl3): δ 1.0 (d, 6H); 2.0 (m,1H); 3.7 (d, 2H); 4.3 (s, 2H), 6.9, d, 2H); 7.2 (d, 2H). Optionally 17may be isolated. The mixture was stirred for about 1 h at roomtemperature (rt) followed by addition of a slight excess of SM1 intoluene and the catalyst added. The mixture stirred at 50° C. for about15 h resulting in pimavanserin being obtained in a quantitative yield(using 1.8 eq CDI) upon aqueous work up.

Optionally SM2b may be treated with a suitable acid such as HCl,optionally isolated, and thereafter proceeding in accordance with theprocedure described. In order to obtain pimavanserin an additionaltrituration of crude pimavanserin was conducted.

Example 6a: Preparation of Pimavanserin Via Urea Derivative

SM2 (1 eq) was treated by urea (2 eq) and 3-methylbutan-1-ol (2 eq) intoluene (10 ml) and heated to 160° C. for 4 h to give isopentyl(4-isobutoxybenzyl)carbamate (18) (M+H=385) which was converted to theisocyanate 19 by distillation. 19 is then converted into pimavanserinaccording to already established methods, for example by reacting 19with a slight excess of SM1 in THF followed by precipitation from EtOHto give pimavanserin.

Example 6b: Preparation of Pimavanserin Via Urea Derivative

SM2 is brought into contact with a small excess of urea, and thereafterthe mixture stirred at elevated temperature such as 150° C. in order toobtain I10. To I10 in toluene SM1 was added and the reaction proceededas described above. The mixture was stirred until consumption of SM1 inorder to give pimavanserin.

Example 6c: Preparation of Pimavanserin Via Second Urea Derivative

SM1 is brought into contact with a small excess of urea mixed atelevated temperature such as 150° C. to obtain I11 which thereafter ismixed with SM2. The mixture was stirred until consumption of SM2 inorder to give pimavanserin.

Example 6d: Preparation of Pimavanserin Using a Carbamate Reagent

SM2 is brought into contact with a small excess of ethyl carbamate, andthereafter the mixture stirred followed by addition of SM1. The mixturewas stirred until consumption of SM1 in order to give pimavanserin.

Optionally other alkyl carbamates such as methyl carbamate can be used.

Example 6e: Preparation of Pimavanserin Using a Reversed CarbamateReagent

SM1 is brought into contact with a small excess of ethyl carbamate, andthereafter the mixture stirred followed by addition of SM2. The mixturewas stirred until consumption of SM2 in order to give pimavanserin.Optionally other alkyl carbamates such as methyl carbamate can be used.

Optionally I11 (obtained for example as described above) may be reactedwith 4-isobutoxybenzaldehyde (described herein) using titaniumisopropoxide (slight excess) in THF and refluxing for 6 h to givepimavanserin followed by treatment by sodium borohydride; or I11 may bereacted with (4-isobutoxyphenyl)methanol (commercially available) using(Pentamethylcyclopentadienyl)iridium(III) chloride dimer as a catalyst,in tert-amyl alcohol and sodium hydroxide at 60° C. for 16 h to obtainpimavanserin.

NMR of I11 (400 MHz, DMSO-d₆) δ 7.30-7.21 (m, 2H), 7.15-7.04 (m, 2H),5.97-5.92 (m, 2H), 4.37 (s, 2H), 3.82 (td, J=11.4, 5.3 Hz, 1H), 2.68(dq), J=10.9, 2.6, 1.8 Hz, 2H), 2.08 (s, 3H), 1.87 (td, J=11.6, 2.6 Hz,2H), 1.59-1.37 (m, 4H).

Example 7—Process Scale Preparation of Pimavanserin and PimavanserinTartrate

SM2b (350 g) dissolved in water (700 g) was added to toluene (1780 g),followed by potassium carbonate (200-220 g) in water (467 g). The vesselcontaining the potassium carbonate was washed with 87 g water and addedto the mixture containing SM2b. Phenyl chloroformate (252-260 g) wasadded over 1.5 h while maintaining a temperature between 15-30° C. Thevessel containing the phenyl chloroformate was washed with toluene (47g) and added to the mixture containing SM2b followed by stirring atabout 20-30° C. for 1-2 h. The mixture was heated to 50-60° C. andsolvent was distilled off (about 940 g) from the organic layer. Themixture was heated to about 70° C. and heptane (1000-1200 ml) added at arate maintaining the temperature at or above 65° C., and thereafterstirred at 70° C. for 1 h. Thereafter the mixture was cooled to ambienttemperature and stirred for 12-18 h, and thereafter filtered. Theproduct was washed, with heptane/ethyl acetate (9:1), and dried to giveabout 400 g of I1.1.

I1.1 (350 g), potassium carbonate (80.0-90 g) were suspended in toluene(about 1600-2000 g), and SM1 (e.g. prepared as outline in Example 1a orb) (272.9 g) was added and the vessel containing SM1 was washed withtoluene (about 140 g), added to the mixture containing I1.1. The mixturewas heated to about 60-70° C. for 4-8 h. Thereafter the mixture wascooled to about 50° C., and washed with 30% sodium hydroxide (195 g) inwater (1376 g). The organic layer was washed with water (805 g) at atemperature of about 50° C. and thereafter solvent was distilled off(about 1200 g), followed by addition of ethyl acetate (483 g) andheptane (1931 g). The mixture was heated to about 60° C. for 1 h andallowed to cool to 20° C. at a rate of about 0.2° C./min, and thereafterstirred for 3-5 h followed by filtering and washing with 20 w % ethylacetate in heptane (604 g). The obtained compound of Formula (I)(pimavanserin) was dried at about 50° C. for 12 h (<50 mbar).

The compound of Formula (I) can be converted into a hemi-tartrate salt.Examples of the salt formation are: suspending the compound of Formula(I) (400 g) in methyl ethyl ketone (MEK, 2368 g), heat to dissolve atabout 50° C. and filter into a reactor through a 1 μm filter washingwith MEK (95 g). (L)-tartaric acid (70.22 g), dissolved in MEK (758 g)and methanol (112 g), heated to about 50° C. and filtered through a 1 μmfilter into a vessel. Seed crystals (15.7 g) of pimavanserin tartrateform C was added to the mixture and the (L)-tartaric acid solution addedover approximately 2 h while a temperature of above about 45° C. wasmaintained. Solvent was distilled off, and MEK (804 g) added andadditional solvent distilled off under vacuum at a temperature between20 and 50° C. The mixture was heated to about 60-75° C. and maintainedfor 1-14 h and thereafter cooled to a temperature of about 5° C. overapproximately 6 h, followed by stirring for about 2 h, and thereafterfilter washed with MEK. The product was dried at about 50° C. to give atartrate salt of the compound of Formula (I) as polymorphic Form C.

The formation of the hemi-tartrate salt of the compound of Formula (I),as well as polymorphic Form C, may be performed as an integrated processstep, or as a separate subsequent process step. Hence Form C can beobtained in a direct formation from pimavanserin without the need forintermediate isolation.

Optionally the tartrate salt of the compounds of Formula (I) may beobtained by a preparing a solution of tartaric acid in ethanol byheating at about 40-50° C., and part of the solution added the compoundof Formula I in ethanol (prepared according to any one of examples 1-6).The solution was seeded with pimavanserin tartrate, e.g. a mixture ofpolymorphic forms, and stirred the slurry for 30-60 min at 40-50° C.Thereafter the rest of the tartaric acid solution was added and theslurry stirred for additional 30 min. The reaction mixture was cooled to0-10° C. over 5-6 h and stirred at this temperature for 1 h. The productwas isolated by centrifugation and washed with cold ethanol. The crudeproduct thus obtained was dried under vacuum at 45° C., sieved at 3 mmfollowed by another drying in order to obtain pimavanserin as a salt.

All publications, patents and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of the teachingsof this invention that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims.

1. A method of preparing pimavanserin(N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide)or a salt thereof, the method comprising: contacting an intermediateaccording to Formula (A),

with an intermediate according to Formula (B),

or a salt thereof, to produce pimavanserin wherein Y is —NR_(2a),R_(2b);R_(2a) and R_(2b) taken together with the nitrogen to which they areattached form a substituted or unsubstituted heteroalicyclyl, or asubstituted or unsubstituted heteroaryl; R₃ is hydrogen, R₄ issubstituted or unsubstituted aralkyl; X is —NR₂₃R₂₄; R₂₁ is F; and oneof R₂₃ and R₂₄ is hydrogen and the other of R₂₃ and R₂₄ isN-methylpiperidin-4-yl, or both R₂₃ and R₂₄ are hydrogen. 2-24.(canceled)
 25. The method according to claim 1, wherein R₄ is4-isobutoxybenzyl.
 26. The method according to claim 1, wherein theintermediate according to Formula (A) is an intermediate according toFormula (A2)

and the intermediate according to Formula (B) is an intermediateaccording to Formula (B2)


27. The method according to claim 26, wherein Y is a substituted orunsubstituted imidazolyl.
 28. The method according to claim 27, whereinY is an unsubstituted imidazolyl.
 29. The method according to claim 28,further comprising contacting (4-isobutoxyphenyl)methanamine withcarbonyldiimidazole to produce the intermediate according to Formula(A2), and wherein the produced intermediate according to Formula (A2) isintermediate I6:


30. The method according to claim 29, wherein the produced intermediateaccording to Formula (A2) is isolated prior to being contacted by theintermediate according Formula (B2).
 31. The method according to claim29, wherein the (4-isobutoxyphenyl)methanamine is contacted bycarbonyldiimidazole to produce the intermediate according to Formula(A2), which is subsequently contacted by the intermediate according toFormula (B2) in a telescoping synthesis.
 32. The method according toclaim 1, further comprising contacting the pimavanserin produced fromthe previous step with (L)-tartaric acid to produce a pimavanserintartrate salt.
 33. The method according to claim 32, wherein thepimavanserin tartrate salt is a hemi-tartrate salt.
 34. The methodaccording to claim 32, wherein the produced pimavanserin is contactedwith (L)-tartaric in methyl ethyl ketone to produce a pimavanserintartrate salt obtained as a polymorphic Form C characterized by havingan endotherm with an onset of between 167 and 177 C.° as obtained bydifferential scanning calorimetry (DSC).
 35. The method according toclaim 34, wherein the DSC shows no peak between 120 and 140° C.
 36. Themethod according to claim 32, wherein the produced pimavanserin isisolated prior to being contacted with (L)-tartaric acid to produce thepimavanserin tartrate salt.
 37. The method according to claim 32,wherein the produced pimavanserin is not isolated prior to beingcontacted with (L)-tartaric acid to produce the pimavanserin tartratesalt.
 38. The method according to claim 1, wherein the intermediateaccording Formula (A) is contacted with the intermediate according toFormula (B) in the presence of a base.
 39. The method according to claim38, wherein the base is selected from the group consisting of triethylamine, diisopropyl amine, pyridine, alkali metal carbonates, sodiumhydroxide, potassium hydroxide, sodium phosphate and potassiumphosphate.
 40. The method according to claim 39, wherein the base issodium carbonate or potassium carbonate.
 41. The method according toclaim 39, wherein the base is potassium carbonate.